5-year PFS Research Articles

Bortezomib-Cyclophosphamide-Dexamethasone (VCD) Vs Bortezomib-Lenalidomide-Dexamethasone (VRD) in Newly Diagnosed Multiple Myeloma: A Matched Real-World Analysis from the Balkan Myeloma Study Group (BMSG)

Bortezomib-based triplets have been the mainstay of primary therapy for patients with newly diagnosed symptomatic myeloma (NDMM) for more than a decade. Bortezomib with dexamethasone and cyclophosphamide (VCD or CyBorD) has been a very popular regimen with significant activity and favorable toxicity profile, especially for patients with renal dysfunction and also in a resource poor setting. The combination of bortezomib with lenalidomide and dexamethasone (VRd) is widely used in US and many European countries, especially after the results of phase 3 studies which used this regimen as induction therapy before HDM/ASCT (IFM2009, DETERMINATION) and a prospective comparison to Rd in patients with non-immediate intent to transplant (SWOG S0777). EHA/ESMO guidelines recommend VRd (or VTD-Daratumumab) as preferable options and VCd as alternative if the other two regimens are not available; however, VCd and VRd have not been compared directly in a prospective randomized trial but only in retrospective studies, from referral centers. We aimed to compare the outcomes of patients treated with VCd or VRd in a real-world setting. The analysis included 1911 NDMM patients treated with VCd (N=1326) or VRd (N=585) with available data in the BMSG database. Initially, we compared the disease and patient characteristics of the two groups: VRd treated patients were more often >65 years (48% vs 36%, p<0.001) and had less often ISS-3 disease while VCd treated patients had more often hypercalcemia (30% vs 18%, p<0.001), eGFR<30 ml/min/1.73 m2 (26% vs 10%, p<0.001), serum LDH>ULN (27% vs 16%, p<0.001), lower platelet counts (<130 K/uL) (12% vs 6%, p=0.001), anemia (Hgb<10 gr/dl) (44% vs 36%, p=0.001), ECOG performance status (PS) 3-4 (16% vs 11%, p=0.011). HDM was used as consolidation in 52% of VCd treated vs 32% of VRd treated patients (p<0.001) while maintenance therapy after induction or consolidation was given in 46% vs 64% respectively (P<0.001). ISS stage distribution was significantly different (21%, 29% and 50% were ISS-1, -2 & -3 in VCd vs 37%, 33% & 30% for VRd treated pts, p<0.001) and high risk cytogenetics frequency was similar (22% vs 22.5%, p=0.787). Distribution to R-ISS-1, -2 & -3 stages (VCd: 8%, 77% and 15% vs 18%, 71% and 11% for VCd and VRd, respectively, p<0.001) and R2-ISS-I, -II, -III & -IV (VCd: 11.5%, 22%, 48.5%, 18% and VRd: 17.5%, 26%, 39% and 17%, p=0.009) were different. A response (≥PR) after induction with VCd and VRd was recorded in 88% and 97% of evaluable patients (N=1653) (p<0.001) with CR/VGPR in 51.5% and 69% (p<0.001). Median PFS was 31 vs 44 months (p<0.001) and 5-year OS was 63% vs 73% with VCd and VRd respectively(p<0.001). We then performed a multivariate analysis that included major prognostic factors that differed between the two groups (age, ISS-3 disease, eGFR<30, LDH, PS, HDM use, HR cytogenetics, use of maintenance): VRd was independently associated with higher probability of CR/VGPR (OR: 2.3, p<0.001), improved PFS (HR: 0.718, p=0.024) and improved OS (HR:0.61, p=0.023). In ASCT-treated patients that also received lenalidomide maintenance, 3-year PFS was 61% vs 84% (p<0.001) and 5-year OS was 79% vs 93% (p=0.003) for VCd and VRd respectively. However, the significant differences in the baseline disease and clinical characteristics between the two groups do not allow direct comparisons. In order to decrease bias, we performed an analysis in pts matched for age, country, eGFR, ISS stage, cytogenetics, HDM and maintenance use. The matched groups included 182 patients each (N=364): ORR was 90% vs 98% (p<0.001), CR/VGPR rate was 51% vs 71% (p=0.001), 3-year PFS rate was 55% vs 69% (p=0.016) and the 5-year OS was 70% with VCd vs 71% with VRd (p=0.269). In the ASCT-treated subgroup, 5-year PFS and OS were 54% vs 69% (p=0.086) and 87% vs 94% (p=0.335) for VCd vs VRd. In conclusion, VCd remains an important regimen for the management of NDMM, especially in a resource poor setting and in special circumstances, although VRD is associated with a significant reduction in the risk of primary induction failure and deeper responses. In matched analysis, VCd does not seem to be associated with significantly inferior OS compared to VRd, which is associated with better responses and longer PFS. With the implementation of new drugs, such as monoclonal antibodies, VCd backbone is a reasonable option for patients that do not have access or do not tolerate VRd or in newer combinations in the upfront setting.

Clinical Characteristics and Outcomes of Limited Stage High Grade B-Cell Lymphoma with MYC/BCL2 and/or BCL6 Rearrangements: A Single Center Experience

Introduction: High grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements (HGBCL MYC/BCL2 and/or BCL6-R) is a group of aggressive lymphomas associated with poor outcomes when treated with R-CHOP. Most HGBCL present in advanced stage and have a high risk for CNS relapse. MYC partner (Immunoglobulin (IG) vs. Non-IG) status has been correlated with clinical outcomes. Recent data suggests that MYC/BCL6 translocations may not portend the same inferior outcomes as MYC/BCL2-R and that limited stage HGBCL MYC/BCL2-R may have similar PFS and OS when treated with intensive chemotherapy vs. R-CHOP. In this study, we aimed to build upon the paucity of data available by describing the clinical characteristics of limited stage HGBCL including the risk of CNS relapse, and the role of MYC partner on clinical outcome. Methods: We performed a retrospective analysis of pts with newly diagnosed HGBCL MYC/BCL2 and/or BCL6-R at MSKCC from 1/2010 to 9/2022. All pts had pathological confirmation conducted at MSKCC. Patient demographics, disease/treatment history, clinical response (CRR and ORR), PFS and OS were extracted from electronic medical record. Stage modified IPI (smIPI) [age>60, elevated LDH, Stage II/IIE, ECOG ≥2] and Stage Adjusted IPI (stIPI) [age >60, elevated LDH, ECOG ≥2] were calculated. PFS and OS were estimated using the Kaplan-Meier method, and comparisons were made using log-rank test. Associations between survival outcomes, clinical, and treatment characteristics were evaluated using Cox regression models, from which HRs and corresponding 95% CIs were obtained. FISH for MYC partner was performed on archived tissue. Results: A total of 188 patients were identified with HGBCL MYC/BCL2 and/or BCL6-R. Nine pts were excluded due to limited information, and 41 pts were identified as having limited stage disease. Median age at diagnosis was 60 years (22-88 years), 63% had Stage II disease, 34% had extranodal involvement of which 50% involved the GI tract, 65% had a smIPI of 0-1, 75% with stIPI of 0-1, and 24% had transformed disease. Regarding rearrangement status, 41% of patients had MYC/BCL2-R 22% were characterized by MYC/BCL6-R and 37% had MYC/BCL2/BCL6-R . The median diagnosis-to-treatment interval was 23 days. First-line treatment included DA-R-EPOCH (76%), R-CHOP (20%), R-CODOX-M-IVAC (2%), and R-GCVP (2%) (median of 6 cycles). Twenty-seven percent received radiation. Thirty-two percent of patients received CNS prophylaxis, with the majority receiving IT-chemotherapy alone (median of 4 doses). After a median follow-up of 48 months, the median PFS was not reached and median OS was 63 months, respectively (Table 1). The 2-year PFS and OS were 56% and 67%, respectively. The ORR and CRR were both 73%. Fifteen patients had relapse/refractory disease, with the majority being primary refractory (12/15). Seven pts received salvage with ASCT (n=1), CAR T-cell therapy (n=4) or both (n=2). Eleven died due to progressive disease. No CNS relapses occurred. MYC/BCL2-R had inferior outcomes with a median PFS of 17 months (95% CI 6.4-27.6) as compared to MYC/BCL6-R (not reached) (P=0.0079, Fig 1), and there was no additional impact on PFS and OS if MYC/BCL2/BCL6-R was present compared to MYC/BCL2-R alone. In a univariate analysis, elevated LDH (p=0.04), MYC/BCL2 (p=0.009), and stIPI ≥2 (p=0.0025) were associated with inferior PFS as well as OS. On the contrary, extranodal disease, age, ECOG ≥2, smIPI, bulky disease, consolidation with radiation, transformed disease, and intensive chemotherapy (DA-R-EPOCH) did not impact outcome. MYC partner evaluation and copy number analysis (n=31) is in progress. Conclusions: In our series,pts with limited stage MYC/BCL2-R had poor outcomes while MYC/BCL6-R experienced favorable outcomes. There was no additional prognostic impact when BCL6-R is present with MYC/BCL2-R . This adds to the growing evidence that MYC/BCL6-R is not a poor prognostic factor in HGBCL. Primary refractory disease defines the majority of treatment failures in our study and is associated with dismal outcomes, although our CAR-T cell experience was limited due time period of this study. Despite this, our results emphasize the need for improved treatment strategies for this patient population. Ongoing analysis of MYC partner and copy number analysis may reveal genetic mechanisms driving outcomes. No CNS relapses occurred, suggesting that CNS prophylaxis can be safely omitted for the majority.

Outcomes with MEK Inhibitor Therapy Among Adults with Langerhans Cell Histiocytosis (LCH): A Multi-Institutional Study from the Adult LCH Working Group for the Histiocyte Society

Purpose: The discovery of MAPK/ERK pathway mutations has led to the approval of MEK-inhibitor (MEKi) cobimetinib in histiocytic neoplasms. However, the pivotal clinical trial that led to the approval of cobimetinib included only 4 patients with Langerhans cell histiocytosis (LCH). Therefore, there is a need to define outcomes with MEKi therapy in patients with LCH. We undertook a multi-center collaboration through the Adult LCH Working Group for the Histiocyte Society to address this gap in knowledge. Methods: Adults with LCH who received MEKi therapy were included from five institutions. Objective response rate (ORR) was evaluated using PET/CT criteria, and CT/MRI if PET scan was not available; response categories were categorized into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Progression-free (PFS) and overall survival (OS) were calculated from the time of targeted therapy initiation. Risk organ disease was defined as liver, spleen, or bone marrow involvement. Results: 25 adults with LCH were included in this study; median age at MEKi initiation 43y (range, 18-85). Most common systems involved at diagnosis were bone (52%), pituitary (44%), and lung (36%). Risk organ involvement was observed in 7 (28%, 6 liver, 1 liver and spleen) and 2 (8%) patients had intra-axial CNS involvement. Median lines of prior therapy received were 2 (range: 1-5), and 4 (16%) patients received MEKi in first-line. MAPK/ERK pathway status was assessed via target capture next generation sequencing (NGS) in 22 (96%) cases. Amongst those who underwent NGS, alterations identified included: BRAF V600E (2/22, 9%), BRAF deletions (11/22 50%), MAP2K1 or MEK mutations (4/22, 18%), and MAPK1 or ERK2 (n=1, 5%). Overall, 5 patients also received BRAF inhibitors (4 patients as first therapy prior to MEKi and 1 concomitantly due to BRAF V600E positive melanoma). Specific MEKi agents utilized included cobimetinib (n=13) and trametinib (n=12). Among the response evaluable patients (n=23), ORR to MEKi treatment was 78% (9 CR, 9 PR, 4 SD, 1 PD). Among the 7 patients with liver involvement, responses were seen in 2 (29%) cases. ORR did not significantly differ according to mutation status among those with NGS data (78% MAPK mutated vs. 100% unmutated; p=1.0). In this subcohort, all of the 4 cases that did not respond to MEKi had liver involvement; 3 had BRAF deletions (2 SD and 1 PD), and one had MAPK1 mutation (SD). Median follow-up duration after MEKi initiation in the entire cohort was 18 months (95% CI 6 - 30). The median PFS and OS were not reached; 2-year PFS and OS were 78.1% and 79.9%, respectively (Figure 1A). The median PFS was much shorter in those with liver involvement (7 months [95% CI 0 - 14]) compared with those without liver disease (not reached [95% CI 19-not reached] P=0.047; Figure 1B). PFS did not differ significantly between MAPK pathway mutated and unmutated patients (p=0.34) Adverse events (AEs) were reported in 36% (n=9) and most commonly included rash (n=5) and fatigue (n=3). Four patients experienced grade 3-4 AEs including rash, fatigue, and thrombocytopenia. Common causes of MEKi discontinuation included AEs (n=3), progression (n=2), and drug holiday (n=2). At last follow-up, 5 patients died and 18 remained on MEKi. Death was attributable to LCH (n=3), concomitant malignancy (n=1), or unknown causes (n=1). Conclusions: In our multi-institutional study of adults with LCH, we found MEKi therapy to be highly efficacious. However, liver involvement correlated with a lack of response and worse PFS, while mutational status did not. Future studies are needed to evaluate optimum treatment for high-risk subgroups of LCH like liver disease.

Real-Life Experience with Lenalidomide Plus Anti-CD20 Antibodies for the Treatment of Patients (pts) with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL)

Introduction: The combination of lenalidomide and anti-CD20 antibodies (Ab) is an accepted treatment for R/R iNHL and often used as comparator in registration-directed clinical trials. In pts with R/R marginal zone lymphoma (MZL) or follicular lymphoma (FL) lenalidomide plus rituximab (R2) produced a median PFS of 27.6 months and 5-year OS 83.2% (Leonard, ASH 2022). Similarly, lenalidomide and obinutuzumab (RO) led to high PFS and OS rates in pts with R/R FL (2-year PFS 65% and OS 87%, Morschhauser, Lancet Haematol. 2019). Whether these results are reproducible in clinical practice is unknown. Methods: We retrospectively analyzed our institutional experience in patients with R/R FL or MZL treated at MSK with R2 or RO identified on our electronic lymphoma database. Patients with previous history of histological transformation (HT) or who received R2/RO in combination with other agents were excluded. Planned lenalidomide starting dose was 20 mg orally daily for 21/28 days for twelve 28-day cycles; dose adjustments were considered in case of impaired renal function per standard practice. Rituximab was administered at 375 mg/m2 weekly for 4 weeks, then every 28 days for five 28-day cycles; and obinutuzumab at 1000 mg on D1, 8, and 15 of C1, then on D1 of each 28-day cycle for 6 cycles. Response was assessed according to the 2014 Lugano criteria; for splenic MZL and extranodal MZL patients, the ESMO guidelines were adopted to assess disease response (Zucca, Annals of Onc. 2020). PFS was defined as the time from treatment initiation to disease progression or death, and OS as the time from treatment initiation to death from any cause. Patients undergoing autologous (auto) or allogeneic (allo) stem cell transplantation (SCT) were censored at that time. Results: 85 pts were treated between June 2013 and December 2022. Median age was 65 years (range 39-94); 71 patients (83.5%) had FL and 14 (16.5%) had MZL, and 18 patients (21%) had bulky disease (>7cm). The median number of prior therapies was 2 (range 1-8), 39 pts (46%) had ≥3 prior treatments, and 44 (53%) were refractory to their last regimen; 86% received R2 and 14% RO (Table). At the time of this analysis, pts had received a median of 9 cycles and 8 (10%) received more than 12 cycles. Eight (9%) pts are on therapy, 35 (41%) completed the planned treatment, 17 (20%) discontinued due to progression, 4 (5%) due to adverse events (AEs), 5 (6%) because they underwent auto- or allo-SCT, and 7 (8%) by medical decision, while in 9 cases (11%), treatment was prematurely discontinued in pts who achieved complete response (CR) after 6 cycles. Lenalidomide dose reduction was required in 47 pts (53%) due to non-hematologic AE (20 pts), cytopenia (12), impaired renal function (6), or other reasons (9). AEs of any grade occurred in all but one pt. The most frequent were neutropenia (45%), fatigue (47%), thrombocytopenia (33%), constipation (32%), rash (25%), and anemia (22%). Five patients (6%) developed a second cancer, including myelodysplastic syndrome (1), mucoepidermoid carcinoma (1), and non-melanoma skin cancers (3). The median duration of follow-up is 30.8 months. End of treatment disease response was evaluable in 76 patients; the remaining 8 were still receiving treatment at time of data cutoff and 1 discontinued R2 due to grade 3 colitis before the first disease assessment. The overall response rate (ORR) was 66%, with 55% achieving CR. There were no differences in response rates between pts receiving R2/RO in 2nd line or ≥3rd line, or between pts treated with R2 and RO. The median PFS was 21 months, and the 2-year PFS rate was 44.3% (95% CI: 32.7-60.0%). Seventeen pts died, 10 due to lymphoma and 7 due to other causes. HT occurred in 6 pts. The median OS was not reached, and the 2-year OS rate was 84.4% (95% CI: 75.9-92.6%) (Figure). Conclusion: This is the first real-life study of combined lenalidomide and anti-CD20 Ab for pts with R/R iNHL. Efficacy results were comparable to those reported in clinical trials and we observed no new safety signals. Our findings reaffirm the role of lenalidomide plus anti-CD20 Ab in the management of R/R iNHL and help define the benchmark for registration-directed clinical trials that utilize R2/RO as the control arm.

Comparison of Response and Survival Outcomes in Standard- and High-Risk Newly Diagnosed Transplant-Eligible Multiple Myeloma (NDMM) Patients Treated with Lenalidomide, Bortezomib and Dexamethasone (RVD) Versus Daratumumab, Lenalidomide, Bortezomib and Dexamethasone (D-RVD)

Introduction: The combination of lenalidomide, bortezomib, and dexamethasone (RVD) is highly effective for newly diagnosed myeloma (NDMM) patients. However, the addition of daratumumab to RVD (D-RVD) has shown improved depth of response and trend towards PFS benefit. Here, we present a real-world comparison of the largest cohort of patients consecutively treated with either D-RVD or RVD induction therapy in terms of response and long-term outcomes for both standard- and high-risk patients. Methods: 1000 consecutive NDMM patients treated with RVD between January 2007- August 2016, and 326 NDMM patients treated with D-RVD induction therapy from April 2018 - August 2022 were included in this analysis. Daratumumab was dosed either IV or subcutaneously weekly throughout induction; lenalidomide was started at 25 mg on days 1-14, bortezomib 1.3 mg/m2 on days 1,4,8,11 and dexamethasone 40 mg on days 1,8,15 all on a 21-day cycle. Of note, in contrast to GRIFFIN, no consolidative cycles were administered in either DRVD or RVD cohorts, and maintenance therapy for standard risk patients with lenalidomide alone while high-risk MM patients were managed with a triplet induction regimen for 3 years (Nooka et al, Leuk 2014). Demographic and clinical characteristics and outcomes data were obtained from our institutional review board-approved myeloma database and with manual abstraction. Responses and progression were evaluated per International Myeloma Working Group Uniform Response Criteria. Results: Patient characteristics for DRVD vs RVD are found in Table 1. Of note, for DRVD vs RVD, 13.8% vs 15.8% had HR disease, and 16% vs 23.3% had ISS 3 and 4.6% vs 11.5% with RISS 3 disease. 98.6% and 99.7% of patients in the RVD vs D-RVD cohorts underwent ASCT. High-risk disease was defined as presence of del(17p), t(4;14), t(4;16), and complex karyotype. Post-induction overall response rate (ORR) was 99.6% in D-RVD versus 97.1% in RVD, with ≥VGPR rates of 86.5% vs 67.6%, respectively. Post-transplant ORR was 99.3% vs 98.5%, with ≥VGPR rates of 95.6% vs 86.8%, respectively. Though the median follow-up for the Dara-RVD cohort is significantly shorter (19.1 months) compared to the RVD cohort (88.4 months), there is already a PFS benefit demonstrated with quadruplet induction for both standard- and high-risk patients. For all patients, the 2-year PFS and OS for D-RVD vs RVD is 93% and 94% compared to 82% and 91%, respectively. For standard risk patients, the 2-year PFS for D-RVD vs RVD is 94% vs 84%, and for high risk patients, 83% vs 69%, respectively. 2-year OS for standard risk patients was 96% in D-RVD vs 93% in RVD, and 94% vs 79% in HR patients, respectively. OS estimates for HR patients also favored D-RVD, though this is more likely than PFS to be impacted by changes in treatment patterns over the past decade. Conclusions: D-RVD is a highly effective induction regimen that can improve upon outcomes in a historical NDMM population treated with RVD in terms of depth of response and PFS benefit. In the absence of phase 3 data supporting D-RVD vs RVD as standard of care induction, this analysis provides evidence of benefit with the addition of daratumumab to RVD in increasing depth of response, and provides an early glimpse of the promising PFS and OS benefit not only in standard risk patients, but also in patients with high-risk cytogenetic and disease features.

Preliminary Analysis of an Ongoing Phase II Study of Response-Adapted Therapy with Copanlisib and Rituximab for Untreated Follicular Lymphoma

Introduction Frontline therapy for pts with follicular lymphoma (FL) is not based on the molecular profile of the tumor. The PI3K pathway is central to FL biology, but the molecular profile of tumors most sensitive to PI3K inhibition (PI3Ki) is unknown. Copanlisib inhibits both PI3Kα and δ isoforms, and we hypothesized that most pts with treatment naïve FL will have PI3Ki-sensitive tumors and durable complete responses (CRs) may be achievable with short durations of targeted therapy. A gene expression profiling (GEP) predictor utilizes a combination of the expression of 45 selected informative genes and an additional 19 housekeeping genes to identify FL pts at high-risk for early progression within 24 months (Wright et al. ASH Annual Meeting2022). We also hypothesized that copanlisib would induce durable CRs in high-risk pts by the GEP assay. Here, we report a preliminary analysis of an ongoing “window of opportunity” study of copanlisib followed by response-adapted copanlisib and rituximab in treatment-naïve pts with FL (NCT03789240). Methods Pts with untreated grade 1-2, 3A FL, ≥stage 2 are eligible if systemic therapy is indicated: symptoms, progressive lymphadenopathy, or organ compromise. Prior radiation is permitted. Eligibility includes age ≥18 and adequate organ function unless due to lymphoma. HIV, CMV, Hep B or C, and autoimmune conditions are excluded. Pts first receive copanlisib 60mg on days 1, 8, and 15 of a 28-day “window of opportunity” to explore the activity of copanlisib. Following the window, pts receive 6 cycles of copanlisib 60mg on days 1, 8, and 15 of a 28-day cycle along with rituximab 375mg weekly x 4 then on day 1 of each cycle and response is assessed with FDG-PET and CT scans. Pts without response after C6 are taken off study and those with a partial response (PR) can continue for an additional 6 cycles and then stop therapy. Pts who achieve a CR after 6 cycles stop therapy. No maintenance is given. Supportive care includesPCP prophylaxis. The primary endpoint is the CR rate with secondary endpoints of safety, duration of CR, and PFS. Exploratory objectives include identification of a predictive signature of PI3Ki response and the response rate in high-risk pts identified by the GEP assay. Results Twenty-eight pts have enrolled. Median age was 56y (range, 24-80). Seventeen (61%) and 12 (43%) pts had high-risk FLIPI and FLIPI-2 scores ≥3, respectively; 6 (21%) pts had Grade 3A FL, and 17 (61%) pts met two or more GELF criteria. After copanlisib monotherapy in the window, 27 (96%) pts had tumor reductions by CT with a median change of -38% (-62% to +16%) (Figure 1). Among 22 pts who completed 6 cycles, 21 (96%) responded, including 9 (41%) pts with PR and 12 (55%) pts with CR. Of 9 pts with PR who received an additional 6 cycles of therapy, only 1 (11%) converted to a CR bringing the overall CR rate to 59% (13/22 pts). After a median follow-up of 25.8 months, the 2-year PFS was 43.2% (95% CI, 20.7-64.0%). The median duration of CR was 29.7 months (95% CI, 6.3 months - not estimable) with 8 (62%) CRs ongoing (Figure 2). Toxicity was evaluated in 28 pts across 220 cycles. Most common were rash (64%), mucositis (50%), and nausea/vomiting (50%), all G1-2 except 1 (4%) pt with G3 mucositis. The most common ≥G3 toxicities were neutropenia and infections in 5 (18%) pts each. ≥G3 neutropenia occurred in 10 (5%) cycles, responded to therapy interruption and/or growth factors, and did not require dose reduction. Two (8%) pts had copanlisib dose reduced, 1 (4%) each due to rash and mucositis. Therapy was prematurely discontinued in 5 pts: 3 due to COVID-19, 1 for hepatotoxicity that resolved, and 1 due to infusion reaction to rituximab. Nine of 24 (38%) pts were poor risk by the GEP assay. Complete responses were observed in 71%, 67%, and 57% of pts categorized as high-risk by FLIPI, FLIPI-2, and GEP assay, respectively. The CR rate was not affected by bulky disease (any LN >7cm; p=1.00), high-risk FLIPI (p=0.19), high-risk FLIPI-2 (p=0.67), poor-risk GEP (p=1.00), or metabolic tumor volume (p=0.33). Conclusion Nearly all pts with treatment naïve FL have PI3Ki-responsive tumors, and the combination of copanlisib with rituximab achieved a CR rate of 59% at the end of induction therapy. The median duration of CR is nearly 30 months, including ongoing remissions without maintenance. CRs were observed in pts deemed high-risk by the GEP assay and FLIPI score. The safety profile is excellent, with mostly G1-2 toxicities manageable with supportive care.

Improved Outcome of Relapsed/Refractory B-Cell Lymphomas Treated in Phase I Trials with T-Cell Engaging Bispecific Antibodies: A Single Center Experience

Background. Phase I trials usually enroll patients (pts) refractory to standard treatments in order to evaluate the toxicity, pharmacokinetic and preliminary efficacy of new therapeutic agents. However, in the last decade, the emergence of targeted and immune therapies has rapidly expanded the scope and eligibility of phase I trials which currently include also the efficacy assessment. This is particularly evident in B-cell non-Hodgkin lymphomas (NHL), were several treatments proved substantial efficacy in the relapsed/refractory (R/R) setting. Specifically, T-cell based immunotherapy i.e. CART cells and T-cell engaging bispecific antibodies (BSA) showed practice changing results. Aim of this study was to compare the outcome of pts enrolled in phase I trials treated with BSA-based treatment versus all the other treatment modality, with the exclusion of CART cells therapy. Methods. A total of 93 R/R B-NHL pts were enrolled and treated in 11 phase I trials from September 2016 to May 2022 at ASST Papa Giovanni XXIII Hospital of Bergamo, Italy. Investigational treatments included BSA, antibody-drug conjugate, small molecules and immunomodulatory agents, both as single agent or in combination. Clinical characteristics and outcome of patients treated with BSA-based treatment (BSA group) were compared to those of patients treated with the other classes of drug (other group). To assess clinical efficacy, the PFS of the line of treatment prior to enrollment in the phase I trial was compared to the PFS achieved after enrollment. Results. Pts population included 49 pts receiving BSA-based treatment (DLBCL=32, MCL=2, FL=12, MZL=2) and 44 pts other classes of drug (DLBCL=35, MCL=1, FL=8). Median age was 63 years-old (range 19-83) for BSA group and 61 (range 32-79) for the other group. At enrollment, most of the pts were in advanced stage (75% for BSA group and 71% for other group). In the BSA group, the median number of previous treatment lines were 4 (range 2-7) including autologous SCT (28%) and CAR-T cells (4%). In the other group median previous treatment lines were 4 (range 2-9) including autologous SCT (20%) and CAR-T cells (11%). The 2-year PFS in the BSA group was 14% and 9% with the last line of treatment (i.e. prior enrollment) and 53% and 17% after the investigational treatment in the BSA and other groups, respectively (Figure 1). We further analyzed predictor of response and PFS in the BSA group. By univariate analysis, primary or secondary refractory status (P<0.001) were correlated with clinical response. Refractory status (P=0.02), high Ki67 (P=0.016), elevated ferritin (P=0.012), ECOG >1 (P=0.004) and aggressive NHL histology (P=0.026) were correlated with poor PFS. Of note, clinical indices e.g. IPI or FLIPI, did not correlated with clinical outcome. Conclusion. The use of BSA-based treatment markedly improved the outcome of patients with R/R B-cell NHL enrolled in phase I trials, with substantial response rates and durable disease control not commonly seen with other classes of drug.

Impact of Folinic Acid Dosing on Efficacy and Toxicity of High-Dose Methotrexate in Central Nervous System Lymphoma

Treatment of primary central nervous system lymphoma (PCNSL) is centered around a backbone of high-dose methotrexate (HDMTX) with folinic acid (FA) rescue. Higher FA doses were associated with treatment failure in several retrospective studies in acute lymphatic leukemia (ALL), leading to the adoption of lower FA doses in ALL treatment protocols. In PCNSL, FA doses have varied widely, guidelines and consensus statements generally do not address FA dosing, and the effect of FA dosing on treatment outcomes has not been assessed. We retrospectively analyzed the medical records of patients treated at our institute for PCNSL between the years 2014 and 2022 to address this question. Patient characteristics are listed in table 1. Complete dosing data was available for 36 patients. The median number of HDMTX doses administered was 6.5 (range, 2-9;), with an average dose of 3.9 g/m 2 (SD +/- 0.74; range, 2.7-5.0). Per the local protocol, IV FA rescue began 24 hours after each MTX infusion at a fixed dose of 50 mg four times daily and continued until MTX clearance. The average cumulative dose of FA administered per treatment was 322 mg/m 2 (SD +/- 141; range, 140-700). 33 patients (92%) achieved either a partial or complete response on MRI following induction treatment. Three (8%) had progressive disease. 26 patients (72%) proceeded with consolidation treatment. Of these, 16 (44%) underwent autologous hematopoietic stem cell transplant. At a median follow up of 1.6 years (range, 0.3-8.1), 12 patients (33%) suffered progressive disease, disease relapse, or death. The 2-year PFS probability for the entire cohort was estimated at 64.5% (95% confidence interval [CI], 49.4-84.1%), and the 2-year OS as 70.7% (95% CI 56.0-89.2%). In univariate Cox regression analysis, average FA dose during MTX treatment was a significant predictor of both PFS and OS, with hazard ratios (HR) of 2.22 (95% CI 1.39-3.55; p < 0.001) and 2.07 (95% CI 1.31-3.29; p = 0.002), respectively, for each 100 mg/m 2 increase. The FA dose during the first treatment cycle, before assessment of response, was also significantly associated with worse PFS (HR 1.56; 95% CI 1.24-1.96; p < 0.001) and OS (HR 1.41; 95% CI 1.14-1.74; p = 0.001). A trend towards worse PFS and OS was seen with male gender, elevated serum LDH, and deep structure involvement. A Cox multivariate regression analysis using the variables age, gender, serum LDH, deep structure involvement, and the average MTX and FA doses, identified FA dose as an independent prognostic factor for PFS, with an estimated hazard ratio (HR) of 2.23 for each 100 mg/m 2 increase (95% CI, 1.25-3.97; p = 0.006). A smaller effect was seen when the FA dose during only the first treatment cycle was examined (HR 1.55; 95% CI 1.16-2.08; p = 0.003). Involvement of deep structures was also significantly associated with worse PFS, with an estimated HR of 8.59 (95% CI, 1.28-57.5; p = 0.027), and there was a borderline significant trend for worse PFS with male gender and elevated LDH. None of the examined variables were identified as statistically significant predictors of OS in the multivariate analysis. Logistic regression with 2-year PFS as the dependent variable was used to define a cutoff value of 350 mg/m 2 for FA dose. The group of patients who received FA doses above and below this threshold showed significantly different PFS curves (figure 1). The 2-year PFS probability was estimated at 56.6% (95% CI, 35.4-90.5%) for patients who received doses of FA above this threshold, and 70.5% (95% CI, 51.7%-96.2%) for patients who received doses below it. We identified no effect of FA dosing on hematologic, renal, hepatic, or gastrointestinal toxicity at the dose ranges examined. In summary, we found that high FA doses were associated with inferior PFS in PCNSL. Such high doses may be avoided through use of lower individual doses of FA, such as 15 mg/m 2 or 25 mg fixed doses as have been used in some protocols, rather than the 50 mg or higher doses used in our and other's practice. Our conclusions are moderated by the study's limitations, which include a small sample size limited to a single center and a retrospective design. However, they suggest that optimizing FA dosing in treatment of PCNSL might improve treatment efficacy without excess toxicity. Future larger and prospective studies will be required to better define the range of MTX and FA doses at which the balance between prevention of treatment toxicity and preservation of treatment efficacy is preserved.

Lenalidomide Maintenance after VTD Induction and Autologous Stem Cell Transplantation: An Italian Real-Life Study of 558 Patients

According to 2021 ESMO guidelines, treatment of newly diagnosed (ND) transplant eligible (TE) Multiple Myeloma (MM) patients is settled by an induction phase followed by single or tandem autologous stem cell transplantation (ASCT) and Lenalidomide (Len) maintenance. Len maintenance was approved in Italy in May 2018 due to the results of the meta-analysis by McCarthy et al. of three large randomized clinical trials. Before the approval of daratumumab-bortezomib-thalidomide-dexamethasone (D-VTD) regimen, VTD triplet combination was the most used induction regimen across Italian centers. In addition, given the data from the EMN02 trial, in the last years tandem ASCT has been a consolidated practice especially for high-risk cytogenetic patients. However, only a minority of patients enrolled in the meta-analysis of McCarthy received VTD induction and in most of them a single ASCT has been performed. In this context, the aim of this real-life study was to evaluate the efficacy and the safety of Len maintenance after VTD plus single or tandem ASCT in ND TE MM patients. The study cohort included 558 patients with a median age of 59 years (24-74) followed in 21 Italian referral centers. Baseline clinical and biological features are reported in table 1. ISS III and R-ISS III were detected in 111/518 (21.4%) and 44/405 (10.9%) cases, respectively, moreover, 30/327 (9.2%) patients showed R2 ISS stage IV. FISH analysis was available in 408 patients with 70 of them displaying high risk (HR) alterations [including t(4;14), t(14,16) and del17p]. Among the 338 standard risk patients, information about 1q status was available for 320 of them, with 60 patients harboring +1q abnormalities (18.75%). All patients received VTD induction (median number of cycles 4) and single or tandem ASCT was performed in 63.7% and 36.3% of cases, respectively. A median number of 22 cycles of Len maintenance was administered. Complete response (CR) and stringent CR (sCR) rates before starting Len were 31.8% and 14.2%, respectively (overall 46%) and increased with maintenance to 39.6% and 16.6%, respectively (overall 56.2%). Most importantly, 2-year CR and sCR rates in evaluable patients were superimposable (40.6% and 14.9% respectively, 55.5% overall). One hundred ninety-seven patients (35.3%) discontinued treatment, mostly due to progressive disease (134/197, 68.0%). Toxicities were mostly hematological with neutropenia found in 50.4% of cases (grade ≥3 in 17.2%), followed by thrombocytopenia and anemia in 24.4% and 16.1% of cases, respectively (grade ≥3 in 2.1% and 1.8% of cases, respectively). Non-hematological adverse events were primarily gastrointestinal (31.2%, grade ≥3 in 2.3%) and infections (42.3%, grade ≥3 in 3.9%) while skin related disorders affected 7.9% of patients. With a median follow up of 30 months, the 2-year PFS and OS from starting maintenance were 80.6% and 96.7%, respectively. No significant PFS difference was found according to age (>65 years vs ≤65 years, p=0.5924) or ASCT (single vs tandem, p=0.4694). Patients with low-risk disease including ISS I and R-ISS I showed improved PFS as compared to patients with ISS >I and R-ISS >I (2y PFS 84.6% vs 76.6%, p=0.0587 and 87.8% vs 72.7%, p=0.0195, respectively). By R2-ISS, low risk disease (R2-ISS I) confirmed a better outcome as compared to R2-ISS II-III (2y PFS 88.9% vs 72.2%, p=0.0333) and to R2-ISS IV (2y PFS 47.2%, p<0.0001). Finally, considering cytogenetic risk status, standard risk patients displayed a significantly prolonged PFS as compared to high-risk patients (2y PFS 81.6 % vs 56.3%, p<0.0001) and an improved although not significant outcome than patients harboring isolated +1q (2y PFS 77.2%, p=0.09). Moreover, we demonstrated that the accumulation of HR cytogenetic abnormalities reduces patients' outcome, in detail the PFS of patients with at least 2 HR abnormalities was significantly lower than patients with only 1 and without HR aberrations, respectively [2y PFS 44.8% (≥2) vs 73.5% (1), p=0.0301, and 2y PFS 44.8% (≥2) vs 82.8% (0), p<0.0001, figure 1]. To our knowledge, this is the first study evaluating the safety and efficacy of Len maintenance after VTD plus single or tandem ASCT. Our results provide evidence that patients with clinical and biological low risk disease, and more specifically those with R2- ISS I, benefit the most from Len maintenance with a favorable safety profile.

External Validation of the Advanced-Stage Hodgkin Lymphoma International Prognostic Index (A-HIPI): Strong Calibration in the Brazilian Prospective Hodgkin Lymphoma Registry

Background: To be useful across the broadest range of patients and clinical settings, clinical prediction models should be externally validated in different data sets and clinical settings and refined over time. In 2022, the HoLISTIC Consortium (www.hodgkinconsortium.org) developed and validated the A-HIPI model via TRIPOD guidelines for adults 18-65 with advanced stage classic Hodgkin Lymphoma (AS-HL) (Rodday et al., JCO 2023). The A-HIPI model, based on individual patient (pt) data from more than 5000 patients (pts) from North America, Europe, and Australia, predicts progression-free survival and overall survival within the first 5 years (PFS5 and OS5) based on pre-treatment pt and disease characteristics (www.qxmd.com/calculate/calculator_869/a-hipi). In collaboration with Brazilian clinical experts and researchers, we describe the performance of the A-HIPI in the Brazilian Prospective HL registry. Methods: The Brazilian Prospective HL registry (NCT02589548) was originally established in 2009 with the goal of evaluating risk factors, treatment, and disease outcomes. By 2022, 1357 pts with classic HL were registered with a median follow-up of 5 years for surviving patients (Biasoli I. HemaSphere 2022). 5-year PFS and OS were calculated using the Kaplan-Meier method. Using the methodology for validation and calibration outlined in by Rodday et al., calculated risk scores were calculated for PFS5 and OS5. Harrell c-statistic and the Uno c-statistic were calculated to evaluate discrimination (i.e., differentiation of those at higher risk of having an event from those at lower risk) and plots of deciles of predicted vs. observed outcomes were created to assess calibration (i.e., how similar the predicted absolute risk of the model is to the true (observed) risk in an external cohort). In the primary A-HIPI analysis, laboratory values outside of permitted range were excluded and not imputed. This was checked in sensitivity analysis using multiple imputation for missing values; no substantial differences were noted. Thus, in the current validation, out-of-range lab values were excluded. There were no exclusions in the current analysis for early death, defined as deaths that occurred from the onset of first treatment until 30 days after its end. Pts with HIV were excluded from the assembled cohort. Results: 694 patients with AS-HL with the inclusion criteria of the original study were included in the present study. The median age was 30.9 years (range, 18-65) at diagnosis with 46% of the pts being female. 230 (33%) patients were classified as Stage IIB, 190 with Stage III (27.4%), and 274 (39.5%) with Stage IV. Bulky disease (>10 cm) was present in 226 patients (33%). Median hemoglobin was 11.6 g/dL (8-16.3), median albumin 3.63 g/dL (1.41-5.46), and median lymphocyte count was 1.5 x 10 3 µL (0.10-4.76). The 5-y PFS (PFS5) in the A-HIPI Brazilian validation dataset was 68.4% (95% CI: 64.7-71.9%) and the 5-y OS (OS5) was 86.0% (95% CI: 82.8-88.6).Harrell c-statistics for the A-HIPI model were 0.60 (95% CI, .56-.64) for 5-year PFS and 0.69 (95%CI, .64-.74) for 5-year OS and Uno c-statistics for the A-HIPI model were 0.63 (95% CI, .58-.68) for 5-year PFS and 0.72 (95%CI, .65-.78) for 5-year OS. Calibration plots (see figures) show the predicted A-HIPI model estimates were well calibrated with the observed outcomes in the Brazilian HL registry. Conclusions: Despite important differences between the original development cohort for A-HIPI and the Brazilian registry in patient and clinical characteristics (e.g., younger age at diagnosis, greater proportion of Stage IV disease) and the well characterized impact of income maldistribution and socio-economic status on clinical outcomes (Biasoli et al., Int J Cancer 2018), the A-HIPI clinical prediction tool performed well in the Brazilian Prospective Registry. This included evidence of adequate discrimination and calibration. Future studies are planned, including the impact of treatment selection and response, use of interim imaging, and supportive care may underscore important differences in outcomes among adults with AS-HL.

A Retrospective Study of Extracorporeal Photopheresis (ECP) in Treatment of Cutaneous T-Cell Lymphoma (CTCL) Evaluating Global, Skin and Blood Responses

Introduction: Cutaneous T-cell lymphoma (CTCL) is a rare form of T-cell lymphoma involving the skin in early stage, and blood, lymph nodes, and viscera in more advanced stages. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common subtypes of CTCL. Patients (pts) with advanced stage (AS)-MF and SS can have severe symptoms including erythroderma, pruritus, desquamation, and have a poor quality of life. Extracorporeal Photopheresis (ECP) was approved by FDA for CTCL in 1988. It is the recommended frontline therapy for SS and is also often used in AS-MF. ECP works by immunomodulatory mechanisms and has minimum side effects. However updated data is lacking on the efficacy of contemporary ECP. Most of the studies were published years ago and did not stage pts and evaluate responses using the current criteria. Blood response was not evaluated in most studies. Besides, ECP techniques including the administration of methoxsalen have changed. Seeking to understand the efficacy of ECP in current practice, we conducted a retrospective study including CTCL pts treated with ECP at Moffitt Cancer Center (MCC), FL, USA in the past 13 years. Methods: Pts with MF or SS who started ECP at MCC after Jan. 2010 were included. In our practice, pts are typically started on ECP alone. A systemic therapy is added in ~ 3 months when a pt does not respond. Response in blood and skin were evaluated every 3 months. Results: A total of 39 pts were included. 23 (59%) were male; 31 (82%) were Caucasian, 4 (11%) were African-American. When starting ECP, 33 (89%) had stage III/IV disease; 30 (77%) had erythroderma; 10.3%, 33.3% and 56.4% of pts had B0, B1 and B2 disease, respectively (Table 1). 18 (46.2%) pts achieved a best global response of complete response (CR), and 12 (30.8%) achieved partial response (PR). The median time to first global response was 6.5 months (range 3.2-19.8 months). At 3 months 28 pts were on ECP alone and 11 were on concurrent systemic therapy including: Interferon (4), retinoid acid (3), romidepsin (3), and pralatrexate (1). At 6 months 20 pts were on ECP alone and 19 were on concurrent systemic therapy including interferon (7), retinoid acid (4), Romidepsin (4), and 1 patient for each of mogamulizumab, vorinostat, methotrexate and interferon + retinoid acid. When evaluated at 3 months, the overall response rate (ORR) in skin was 8/39 (20.5%) in the entire cohort, and 5/28 (17.9%) in pts not on concurrent systemic treatment. When evaluate at 6 months the skin response rates were 16 (41.0%) and 9 (45.0%) in pts with and without concurrent systemic treatment, respectively. The ORR in blood at 3 months was 19/39 (48.7%) in the entire cohort and 13/28 (46.4%) in pts on ECP alone; at 6 months, the ORRs in blood were 25/39 (64.1%) and 13/20 (65%), respectively. With a median followup of 43 months, the median PFS was not reached (NR). The 5-year PFS rate was 58%. At the last followup, 7 pts who were on ECP alone were in CR, and 3 in PR. The response rates at 3 months, 6 months and the best response rates were not associated with baseline characteristics including blood stage (B0 vs B1 vs B2), global stage (I/II vs III/IV), and concurrent systemic therapy (p>0.1 for all, table 1, part of the data was not shown). Discussion: Our results showed the contemporary ECP therapy had excellent efficacy in SS and AS-MF (ORR 77%). Many pts achieved durable remission (5-year PFS 58%). However, it took a median of 6.5 months to achieve an objective response. Pts with AS-MF and SS have significant symptoms and poor quality of life. Research is needed to identify treatment combinations with ECP to induce a quicker response. One limitation of our study is, some pts received systemic therapy concurrently with ECP, thus making it difficult to isolate the treatment effect of ECP. As a sensitivity analysis, we evaluated responses of pts on ECP alone in the first 6 months, and in this way decreased the confounding effect. Our study is also limited by the retrospective nature and the limited sample size. Future prospective studies in larger scale are needed to confirm our results.

Impact of Brentuximab Vedotin in Patients with Breast Implant-Associated Anaplastic Large Cell Lymphoma with Capsule Infiltration Requiring Chemotherapy

Background: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon peripheral T-cell lymphoma most frequently arising around a textured surface breast implant. It has been shown that capsule infiltration (T2, T3 and T4 of the TNM staging system) was an adverse prognostic factor. In this context, chemotherapy (with or without brentuximab vedotin [BV]) may be proposed, considering other factors such as metastatic disease or incomplete resection. Furthermore, the need for adjuvant chemotherapy in patients with stage IIA (T4N0M0) and complete en-bloc excision without residual disease is debated. Aim: To assess the management of BIA-ALCL with capsule infiltration, in particular: 1) To assess the impact of BV in those patients; 2) To evaluate the need for adjuvant chemotherapy in patients with stage IIA and complete en-bloc excision without residual disease. Methods: Since 2016, a national multidisciplinary meeting has been implemented by the French National Cancer Institute (NCI) to optimize management of patients with BIA-ALCL, particularly those with advanced disease. Meanwhile, a national registry has been set up by the LYSA, in collaboration with health authorities. Central pathological review has been carried out within the French NCI-labeled Lymphopath network. Results: From 2009 to 2023, 125 patients with BIA-ALCL were recorded, of which 111 (94 from France and 17 from Belgium) had complete data and were included in the present analysis. Overall, median age at diagnosis of BIA-ALCL was 58 years (24-82 years). Reasons for initial implantation were breast cancer reconstruction (n=54; 49%), cosmetic (n=45; 41%) or other (n=12; 10%). The median interval from first implantation to diagnosis of BIA-ALCL was 12.3 years (4-40 years). The median number of implants in the breast involved by BIA-ALCL was 2 (1-8), including at least one silicone implant in 95 (86%) patients, and at least one textured implant in all informative cases (n=102; Most often Allergan Biocell implants). At diagnosis of BIA-ALCL, 78/110 (71%) patients presented with periprosthetic effusion only, 20 (18%) had effusion and a breast mass, 6 (5.5%) had a breast mass only, and 6 (5.5%) had neither. At pathological examination of the capsule, T-stage was T1 (confined to effusion or a layer on luminal side of capsule) in 73/111 (66%) cases, T2-T3 (capsule infiltration) in 5 (4.5%) cases, T4 (lymphoma infiltrates beyond the capsule) in 32 (29%) cases, and unclassifiable in 1 case. Moreover, 18/111 (16%) patients had at least one non-breast extranodal involvement. Among the 36 patients with capsule infiltration (5 T2-T3 and 31 T4), 13 (including 11 T4) were treated with BV-CH(E)P regimen, 12 (all T4) with a CHOP/CHOP-like regimen, and 11 (including 8 T4) did not receive any chemotherapy. The main reasons for receiving chemotherapy were metastatic disease, incomplete resection, or no surgery. Patients who did not receive chemotherapy had a localized disease (3 stage IB/IC and 8 stage IIA) with complete en-bloc excision and no residual disease. Patients treated with BV-CH(E)P regimen and CHOP/CHOP-like regimen had similar characteristics without significant differences regarding age, clinical presentation, stage and surgery. After a median follow-up of 47 months from BIA-ALCL diagnosis, for BV-CH(E)P and CHOP/CHOP-like groups, the respective 4-year PFS rates were 100% and 57% (p=0.01), and the respective 4-year OS rates were 100% and 73% (p=0.07). Regarding the 11 patients who did not receive chemotherapy, 4-year PFS and OS were both 75%, which corresponds to a single event being a death without progression occurring more than 3 years after the diagnosis of lymphoma (4-year lymphoma-specific survival was 100%). Conclusions: 1) In patients with capsule infiltration requiring chemotherapy, BV-CH(E)P regimen was associated with improved PFS and OS compared with CHOP/CHOP-like regimen; 2) Patients with stage IIA and complete en-bloc excision without residual disease had favorable outcome without the need for adjuvant chemotherapy. These results should be confirmed prospectively.

Induction and Maintenance Therapy in Elderly Patients with Mantle Cell Lymphoma: Double-Randomized MCL R2 Elderly Clinical Trial By the European Mantle Cell Lymphoma Network

Background: Mantle cell lymphoma (MCL) formally remains an incurable disease. Recent trials in younger patients have demonstrated the benefit of a cytarabin-containing induction (Hermine, JCO 2022) and a rituximab (Le Gouill, NEJM 2017) as well as a lenalidomide maintenance (Ladetto, Lancet Haematol 2021). The MCL-R2 elderly trial investigated whether an induction with intermediate dose of cytarabine improves long term outcome over R-CHOP alone in elderly patients (>60 yrs). In addition, responders to induction therapy were randomized between a 2 year maintenance with rituximab-lenalidomide (R2) compared to rituximab alone. Here, we present the results of the 2 randomizations. Methods: Patients >60 yrs not eligible for high dose therapy with stage II-IV MCL were included. Initially, patients were randomized between 8 cycles of 3-weekly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or 6 cycles of alternating 3-weekly R-CHOP and 4-weekly R-HAD (rituximab, cytarabine, Dexamethasone). Subsequently, patients in complete or partial remission (CR, CRunconfirmed or PR) underwent a second randomization between rituximab maintenance every 2 months or R2 (lenalidomide 15 mg d2-22 every 4 weeks plus rituximab). Second randomization was stratified for induction regimen, study group, age, MCL international prognostic index (MIPI) and response (CR/CRu vs PR). Both maintenance regimens were continued for 24 months. The primary endpoint was EFS for the maintenance and overall survival for Induction therapy. Results: Out of 624 patients from 7 countries, 620 were randomized for induction, 492 responded (78 % ORR, CR/CRu 41%) and 495 were randomized for maintenance. Median age was 71 yrs, 69% male, 85% stage IV, 47% intermediate and 46% high risk MIPI. Response rate at the end of induction was similar in the 2 groups (OR 88% and 86% in the R-CHOP and R-CHOP/RHAD arm, respectively; CR 33% in both arms). No major safety difference were observed between the 2 induction arms. So far, PFS and OS were not different between the two induction regimen (70.6% vs. 66.8%; p=0.28 and 83% vs. 83% ; p=0.92 respectively: Figure 1A). After a median follow-up of 4.2 years from maintenance randomization, patients in the R2 maintenance arm had a significantly improved PFS in comparison to R alone. The 4-year PFS was 60.9% in the R2 arm vs. 42.9 % in the R arm (p= 0.0002, figure 1B). Adverse events (AEs) were more pronounced in the R2 maintenance arm. Recurrent (> 5%) AEs grade >3 were: neutropenia (50.8% vs 19.2%), respiratory tract infection (6.3% vs. 0.8%), and skin cancer (5.9% vs 3.2%). In 46% of patients in the R2 arm, the dose of lenalidomide had to be reduced at least once. Overall survival (OS) was not different between the two maintenance arms, (R2: 87.6% and R: 85.1% at 2 years). The majority of relapsed/refractory patients were treated with a BTK inhibitor alone or in combination (67.5%; 63% after R-CHOP and 71% after RHOP/RHAD). Conclusions: While no efficacy or toxicity differences were observed between the two induction regimens (8x R-CHOP vs 6x R-CHOP/HAD), the combined R2 maintenance significantly prolonged PFS compared to rituximab alone. However, no difference in OS was observed, and toxicity was increased in the R2 arm. Figure 1: OS(A) stratified by the CHOP and R-CHOP/RHAD arms and PFS (B) stratified by maintenance with rituximab (R) or rituximab-lenalidomide (R2) stratified by the four groups according to induction and maintenance arms.

A Compilation of Experiences in Utilizing CAR-T Cell Therapy for Richter's Transformation

Objective:Even with Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors, the prognosis for Richter's Transformation (RT) remains dismal, with a median overall survival (OS) of only 9-12 months from initial diagnosis. Although there are reports on CAR-T therapy for RT, the sample size is small and the conclusions vary greatly. Methods: We conducted a retrospective investigation of the efficacy of CAR-T cell therapy in treating RT at our center. Each participant provided their informed consent to partake in the “Phase II Clinical Trial of Sequential CAR-T Cell Therapy Targeting Different B-Cell Epitopes for Recurrent, Refractory Aggressive B-Cell Lymphoma”(Protocol number: BR-XG-CART-II, ChiCTR2100055062, Ethical Approval Number 20191225-PJ-003). Before lymphocyte collection, chemotherapy regimen without fludarabine/ Bendamustine is first used to reduce peripheral blood tumor load if peripheral blood tumor cells are higher than 10%. Patients with extramedullary tumor loads of 5cm or larger were treated with tumor reduction chemotherapy between lymphocyte collection and CART cell transfusion. The pretreatment scheme based on Bendamustine or FC scheme was adopted before CAR-T cells were infused. The efficacy and safety of CART cells were observed. Results: Between Feb 1, 2020 and Feb 28, 2023, our center administered CAR-T cell therapy to 16 patients diagnosed with RT, all of whom developed into diffuse large B-cell lymphoma. The patient population had a median age of 59 years (range: 42-69 years), consisting of 62.5% (10/16) males and 37.5% (6/16) females. The ECOG scores varied between 0 and 3. The median number of prior treatment lines was 5 (2-7). 93.8% failed previous BTKis treatment and 75% failed BCL2 inhibitor treatment; 93.8% had undergone chemotherapy (median 6 courses). 1 patient had previously failed universal CAR-T cell therapy, and another relapsed after autologous transplantation. 90% had at least one TP53 abnormality detected by either FISH or second-generation gene sequencing. Extramedullary masses were found in 87.5% (14/16) of patients, with a median maximum diameter of 42.5mm (18-144mm). Masses larger than 5cm were found in 25% (4/16) of cases, marrow involvement was noted in 62.5% (10/16), and cerebrospinal fluid was affected in 18.75% (3/16). None of the patients had central masses observed in their MRIs. During lymphocyte collection, 58.3% of patients showed positivity for peripheral blood tumor cells, with a maximum tumor cell proportion of 5.69%. The median infused CAR-T cell dose was 1.37×10 6/kg. 12 of them were injected with mouse CD19CAR-T, 2 with human CD20CART, and 2 with human CD19CART. CRS occurred in 81.3%of patients, of which, 68.8%were grade 1-2 and 12.5%were grade 3. Central CRS occurred in 6.3% (1/16) of patients. The complete response (CR) rate at the 3-month mark stood at 56.3% (9/16), with an overall response rate (ORR) of 68.8% (11/16). As of July 6, 2023, the median follow-up time was 10.6 months (4.4-33.6m), the 1-year OS was 73.4%, and the 1-year PFS was 68.8%. Median OS and PFS were not reached. One of the five patients who did not respond later underwent allogeneic hematopoietic stem cell transplantation and is still alive. The other four, despite attempts at salvage treatment including second CAR-T cell therapy, all died, with a median OS of only 5.6 months (4.4-8.9m). None of the four patients with extramedullary masses larger than 5cm achieved ORR despite tumor-reducing chemotherapy prior to CAR-T infusion. Only 1 of 3 patients with central involvement achieved CR and experienced grade 3 CRS along the way, while the other 2 did not respond to CAR-T therapy. Among all patients, only one experienced central CRS, and his cerebrospinal fluid showed no signs of tumor cells prior to the administration of CAR-T treatment. A patient who was in CR succumbed to an acute coronary event 19 months following infusion, despite remaining in CR. Conclusion: Even in the presence of TP53 gene abnormalities, resistance to BTK/BCL2 inhibitors, and unsuccessful previous chemotherapy regiments, A single CAR T cell therapy can result in CR in more than half of RT patients. Nonetheless, the prognosis remains bleak for patients presenting with large tumor masses and central nervous system involvement, despite having received chemotherapy aimed at reducing tumor size. The outlook is particularly dismal for those patients who fail to respond to CAR-T cell therapy.

Optimizing Resources: Low-Dose Nivolumab Combinations in the Management of Relapsed/Refractory Hodgkin Lymphoma, a Real-World Experience

Introduction:Up to one-third of patients with Hodgkin's lymphoma (HL) are not responsive to first-line therapy or eventually relapse. For these patients, second-line chemotherapy followed by autologous stem cell transplantation (ASCT) represents the standard of care, with better results for those that respond to salvage chemotherapy, usually achieving higher survival after ASCT, however, this strategy is far from perfection. In recent years, immunotherapy has brought with it novel agents, including monoclonal antibodies and antibody-drug conjugates, that have revolutionized the therapeutic landscape for relapsed or refractory Hodgkin's lymphoma (r/r HL). Anti-programmed death protein 1 antibodies (e.g. nivolumab, pembrolizumab) and anti-CD30 drug, brentuximab vedotin (BV), are two popular examples from the above-mentioned drug classes that have proven both acceptable results and exorbitant prices, unsustainable for patients and health systems from Low- and Middle-income countries. Although pivotal trials indicate that the ideal doses for nivolumab use are 3 mg/kg or 240 mg fixed dose, emerging evidence suggests that full receptor occupation can be achieved with lower nivolumab doses and it has been successfully employed for the treatment of hematologic malignancies in doses as low as 40 mg fixed dose. Objective: In this study, we present our real-world experience exploring different combinations commonly used with standard-dose nivolumab, now with lower doses and costs. Methods:We retrospectively analyzed patients that fulfilled the following criteria: ≥16 years old, diagnosis of relapsed or refractory HL, treated with low-dose nivolumab in any flat low-dose (40, 100, or 140 mg) in any combination with other agents. We retrieved data from their electronic medical record and follow-up imaging studies (CT-Scan or PET-CT). We analyzed the response to therapy using the Deauville score. OS and PFS were analyzed with Kaplan-Meier curves. Survival analyses by treatment regimen and nivolumab subgroups were compared for statistically significant differences by means of the log-rank test. A value of p < 0.05 was considered statistically significant for all tests. Results: A total of 23 patients were included in our study. 57% (n = 13) were women. The median age was 27 years (20-30). Complete baseline characteristics are displayed in Table 1. Most of the patients (73%, n = 17) achieved an objective response, 43% (n = 10) a complete response (CR), and 30% (n = 7) a partial response (PR). No statistically significant differences were observed between types of response by treatment group. Most of the patients who achieved a complete response received a combination of Nivolumab + BV. HSCT was possible in most of the patients at the end of the follow-up (n = 17), 11 of them underwent an autologous HSCT and 6 patients received an allogeneic transplantation. Disease course in the cohort is illustrated in Figure 1. The 1-year OS was 94.4% (95% CI = 0.84 - 1) and the 1-year PFS was 89.4% (95% CI = 0.77 - 1). The OS and PFS were analyzed and compared between different treatment regimens prescribed to the patients. No statistically significant difference could be evidenced in the event probability in both OS and PFS (OS p = 0.73, PFS p = 0.78). Nine (39%) patients did not present adverse events. The most common adverse event was nausea (n = 5, 22%). Other adverse events observed in the sample were: pruritus (n = 3), myalgia (n = 3), neuropathy (n = 3), fever (n = 2), and leukopenia (n = 2 ). Lymphopenia, hypothyroidism, rash, dermatosis, asthenia, arthralgia, cough, and dyspnea were presented by 1 patient each. No patients presented grade 3-4 adverse events in our study. Conclusion: In this real-world study, we explored the effectiveness and safety of low-dose nivolumab in different combinations for relapsed or refractory Hodgkin's lymphoma (r/r HL). Encouragingly, most of the patients achieved an objective response making it an effective bridge to the transplant. Low-dose nivolumab combinations demonstrated a manageable safety profile, with only mild adverse events reported. These findings highlight the potential of lower nivolumab doses in cost savings without compromising treatment efficacy.

Phase II Study of Lenalidomide Maintenance after Salvage Therapy for Relapsed or Refractory Peripheral T-Cell Lymphomas

Introduction Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas. Their prognoses are still poor especially after they relapse or become refractory to the first-line treatment. Although salvage chemotherapy followed by autologous stem cell transplantation (ASCT) could be used for those relapsed or refractory patients, a substantial number of patients relapse even after ASCT. Furthermore, ASCT is not always possible because elderly or frail patients are not eligible for high-dose chemotherapy followed by ASCT. Thus, there are limited treatment option for patients who failed after ASCT or ineligible for ASCT because there is no established salvage treatment strategy and the impact of novel therapies in previous trials is unknown. Lenalidomide is widely used for the treatment of B-cell lymphomas as well as multiple myeloma, however, there are a few data about its efficacy in patients with PTCLs. Considering the mode of action is related with the immune modulatory effect on tumor microenvironment, lenalidomide might have a role in the management of relapsed or refractory PTCLs. Thus, we hypothesized that the use of lenalidomide as a maintenance therapy for patients who achieve response after salvage therapy might produce survival benefit comparable to that of ASCT after salvage therapy. Methods This is a prospective, open-labeled, single-arm, multi-center phase II study for relapsed or refractory PTCLs. The inclusion criteria are as follows: 1) Patients should have relapsed or refractory disease after at least one-line of prior chemotherapy; 2) Patients should not be eligible for ASCT; 3) Patients should have any subtypes of PTCLs including PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase (ALK)-positive or -negative anaplastic large-cell lymphoma (ALCL), extranodal NK/T-cell lymphoma (ENKTL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), hepatosplenic T-cell lymphoma (HSTL), and mycosis fungoides (MF). When patients eligible for the study achieve complete response (CR) or partial response (PR) after four cycles of any kinds of salvage chemotherapy, they can receive lenalidomide as a maintenance therapy. One cycle is 28 days consisting of lenalidomide 25 mg (day 1 - day 21). The treatment can be repeated until progression or the occurrence of intolerable toxicities (up to 2 years). The primary end point is 1-year progression-free survival, and the target rate is 35%. Results A total of 58 patients were enrolled between February 2019 and May 2023. The median age was 62 years (range: 20 - 83 years) and male was dominant (male: 35, female: 23). Patients who failed after ASCT or could not undergo ASCT due to their health status participated in the study. Patients with AITL (n = 23) and PTCL-NOS (15) accounted for 66% of patients whereas other subtypes included ENKTL (n = 4), ALK-negative ALCL (n = 3), MEITL (n = 3), HSTL (n = 2) and MF (n = 7). Prior to the maintenance therapy with lenalidomide, their disease status was CR (n = 22, 38%) and PR (n = 36, 62%). At the median follow-up of 20.7 months (95% CI: 17.7 - 23.7 months), seven patients completed the planned treatment of 2 years, and three patients withdrew their informed consents. Disease progression was documented in 21 patients during the maintenance and the other 20 patients discontinued the treatment due to their adverse events. At the time of analysis, seven patients were maintaining their treatments. Out of 36 patients with PR before maintenance, five patients achieved CR and 13 patients showed PR. However, 18 patients showed disease progression during maintenance. On the other hand, only three patients showed disease progression among 22 patients with CR prior to lenalidomide maintenance. Thus, 1-year PFS after enrollment was 49% and the median OS was (34.1 months, 95% CI: 7.9 - 18.6 months, Figure 1). The most common hematologic toxicities were neutropenia and thrombocytopenia; thus, dose-reduction should be done in patients with grade 4 hematologic toxicity. The most frequent non-hematologic toxicities included skin rash (40%), nausea (35%), and diarrhea (20%) however, they were manageable. Conclusions The lenalidomide maintenance might be a feasible and effective treatment approach for patients with relapsed or refractory PTCLs who are ineligible for ASCT or intensive consolidation chemotherapy.

CD19-Directed CAR T-Cells (CD19-CAR) Combined with Acalabrutinib Achieves Durable Remissions in Patients with Relapsed or Refractory (r/r) Mantle Cell Lymphoma (MCL)

Background: MCL is an aggressive non-Hodgkin lymphoma (NHL) subtype which remains incurable despite improvements in progression free survival with consolidative autologous transplant and the introduction of novel targeted therapies [Dreyling et al. Blood 2012]. CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CD19-CAR) has shown durable disease control in r/r MCL, but current standard of care products are limited by high rates of grade 3+ immune-related toxicities [Wang et al. NEJM 2020]. We hypothesized that combining a naïve/stem-memory (T N/SCM) phenotype-enriched CD19-CAR T-cell product with the selective BTK inhibitor (BTKi) acalabrutinib would attenuate the rates of severe toxicities, improve durable remission rates, and obviate the need for indefinite use of acalabrutinib in r/r MCL. Methods: We conducted a phase 1 single center, prospective clinical trial (NCT04484012) evaluating a single infusion of T N/SCM-enriched CD19.28.z.EGFRt-CAR at a target dose of either 2x10 8 (DL1) or 5x10 8 (DL2) CAR+ cells (≤20% lower dose allowed) in combination with ongoing acalabrutinib 100 mg twice daily for patients with r/r MCL after at least 1 prior line of therapy. Patients were required to undergo at least 3 months but less than 7 months of treatment with a BTKi prior to enrollment without evidence of progression and with measurable disease per Lugano criteria. All patients were switched to acalabrutinib for protocol therapy prior to lymphodepletion, and planned to continue until day 180 post CD19-CAR infusion at which time all therapy would be discontinued. We report outcomes from the dose finding portion of the study. Descriptive statistics were utilized for baseline characteristics and survival analyses were calculated utilizing the Kaplan-Meier method. Investigator-assessed response rates were based on Lugano criteria. Minimal residual disease (MRD) status was determined using either multiparameter flow cytometry (FCM) or next-generation sequencing (NGS). Results: To date, 8 patients enrolled and have received CD19-CAR (n=4 at DL1; n=4 at DL2). Manufacturing was successful in 100% of patients. Median time from leukapheresis to product infusion was 53 days (range, 41-114). Treated patients were 75% male; with a median age of 63 years (range, 38-70); and median number of prior therapies of 2 (range, 2-3). All patients had bone marrow involvement, and had high risk features including progression of disease within 24 months (n=6), relapse after autologous HCT (n=2), TP53 mutations (n=6), Ki-67 ≥30% (n=4), and/or complex karyotype (n=1). Prior to enrollment, all patients had received BTKi (n=8 acalabrutinib) for a median of 6.1 months (range, 4.5-7.3). No BTK and PLC-γ mutations were detected in patients with available samples. The combination of acalabrutinib and CD19-CAR was well tolerated; 5 patients (63%; n=1 grade 2; n=4 grade 1) had cytokine release syndrome (CRS), with no severe cases. No patients (0%) had immune effector cell associated neurotoxicity syndrome (ICANS) [Figure 1A]. No patient required corticosteroids for toxicity management, and only 2 patients (n=2/5, 40%) required tocilizumab for CRS. There were no serious adverse events (SAEs), and no treatment discontinuations due to AEs observed. The best ORR was 88% [n=6 CR (75%); n=1 PR (13%)], with median time to best response of 28 days. In those 6 patients who achieved CR, 2 patients were FCM-MRD negative (<10 -4) and 2 were NGS-MRD negative (<10 -6) (n=4/6, 67%) [Figure 1B]. After a median follow-up of 18.5 months (range, 8.3-28.9), 5 of 6 patients remain in CR, while1 patient who achieved an initial CR relapsed at 9.2 months. At 1-year post-infusion, the cumulative incidence of relapse and NRM were 30% (95% CI, 3%-67%) and 0%, respectively. The 1-year PFS and OS were 70% (95% CI: 22%-92%) and 100%, respectively. Conclusion: The combination of CD19-CAR with acalabrutinib was well tolerated and effective, yielding an ORR 88% and MRD- rate 50% in a cohort of patients with high-risk MCL. Notably, CRS events were manageable and low grade, and no ICANS was observed. Enrollment is ongoing in the expansion cohort (DL2), and additional clinical and correlative analyses will be presented at the meeting.

Novel Chemotherapy-Free Initial Treatment of Rituximab Biosimilar Plus Pegylated Interferon α-2b in Pts with Untreated Advanced Indolent B-Cell Non-Hodgkin's Lymphoma: Results of the Ripple 3-Year Follow-up Study

Background: Indolent B-cell lymphoma (iBCL) are clinically heterogeneous and accounts for 10-15% of all kinds of subtypes in NHL in China. Although iBCL have a relatively good survival, majority of these lymphomas is considered incurable. The favorable activity and safety profile of rituximab monotherapy in the initial treatment of iBCL has been proven. Interferon alpha (IFN-α) was effective in modulating immune responses and may enhance the clinical efficacy of rituximab in vitro and in vivo studies. Clinical combination of rituximab and conventional IFN-α was associated with fewer early treatment failures compared to single agent rituximab. Peginterferon-α-2(peg-IFN-α2) has a longer half-life with less toxicity. It is also recommended as one of the therapeutic options for chronic hepatitis B virus (CHB) infection. The RIPPLE study (ClinicalTrials. gov identifier: NCT04246359) was initiated to evaluate the efficacy and safety of rituximab plus pegylated interferon α-2b for treatment-naive patients with iBCL. This publication provides long-term follow-up data. Methods: This trial enrolled pts aged 18-80 years with newly diagnosed iBCL including follicular lymphoma (FL, grade 1-2,3a), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), small lymphocytic lymphoma (SLL). Pts were eligible if they had ECOG ≤ 2, adequate organ function and bone marrow function, and at least one measurable or evaluable lesion. Further eligibility criteria were HBsAg positivity with HBV DNA load <3000 IU/mL prior to study; serum ALT level of <5 times the upper limit of normal. During induction phase, pts received rituximab biosimilar (Henliritux ® Shanghai Henlius Biotech) 375 mg/m 2 intravenous infusion on d1. Peg-IFN-α2b (Pegberon ®, Xiamen Amoytop Biotech) was given at a dose of 135ug, subcutaneously, on d1,8. The combination repeated every 21 days for 6 cycles. Responded pts receive rituximab (every 2 months) plus peg-IFN-α2b (every month) maintenance at the dose described above, for up to 2 years until disease progression and intolerance. Simultaneously, CHB pts orally treated with entecavir continuously. The primary endpoint is ORR assessed by investigators per Lugano 2014 criteria. Key secondary endpoints included TTR, DOR, PFS, OS, HBV DNA load clearance, and safety. Adverse events (AEs) were summarized according to NCI CTCAE v5.0. Results: From September 2018 to July 2021, 57 eligible pts with median age of 54 (range, 29-75) years were enrolled from 6 institutions in China. Thirty (56.1%) are female, 21(36.8%) pts were symptomatic and 22(38.6%) pts with FLIPI score≥3, 6(10.5%) pts suffer from hepatitis B with HBV DNA load <3000 IU/mL at study entry. At cutoff date, there were 26(45.6%) FL (grade 1-2), 21(36.8%) MALT, 7(12.3%) FL (grade 3a) , 2(3.5%) SLL, 1(1.8) LPL pts enrolled. Of 57 response evaluable pts, 38(66.7%) pts achieved an objective response including 29(50.9%) pts with CR based on investigators. ORR were 69.2% (18/26), 71.4% (5/7), 61.9% (13/21), 0, 100% (2/2) and the CR rates were 46.2% (12/26), 71.4% (5/7), 52.4% (11/21), 0, 50% (1/2) for FL (grade 1-2), FL (grade3a), MALT, LPL, SLL, respectively (Figure 1-2). Median HBV DNA load clearance time was 1.8 months (1.3-2.1months), no hepatitis B virus reactivation reported. With median follow-up time was 34.2 months (IQR:26.5-42.3 months), median OS, PFS and DoR was not reached; 3-years OS and PFS rate of whole cohort was 92.5%, 70.4%, respectively (Figure 3 C-D). Median TTR was 3.0months (1.5-5.2months). The most common treatment-emergent adverse events (TEAEs) were hematological relevance toxicities. The most common hematological TEAEs (>30%) were neutropenia 63.2% (36/57), anemia 36.5% (19/57), thrombocytopenia 29.8% (17/57). Non-hematological TEAEs (>10%) were fever (28.1%, 16/57), transaminase elevated (26.3%, 15/57), fatigue (26.3%, 15/57), infusion reaction (21.7%, 10/46). No treatment-related death occurred. Conclusion: Rituximab biosimilar plus pegylated interferon α-2b provided favorable response in newly diagnosed advanced iBCL with mild toxicity. No hepatitis B virus reactivation was observed.

Treatment-Free Remission Era: BCR-ABL1 mRNA Transcript Level

Background: Early acquisition of a deeper molecular response (DMR) and maintenance of a sustained DMR are prerequisites for implementing treatment-free remission (TFR) in CML patients. Earlier identification of patients who have not reached 24-month DMR and timely intervention is particularly important for patients with a strong desire for TFR. Early molecular response (EMR) of BCR-ABL1 mRNA <10% at 3 months after the initiation of TKI therapy is strongly predictive of a 12-month major molecular response (MMR). Whether the EMR <10% is also a good predictor of the 24-month DMR is unknown. Exploring early predictors of 24-month DMR could help guide clinical treatment decisions and advance the implementation of the TFR plan. Aim: Exploring early predictors of 24-month DMR. Methods: We performed a retrospective analysis of all adult patients with newly diagnosed CML-CP in the Department of Hematology at Guangdong Provincial People's Hospital (Guangzhou, China) between Mar 2009 and May 2019. Patients were monitored with BCR-ABL1 mRNA quantitative RT-PCR monthly for the first 3 months of TKI treatment, then every 3 months for a minimum of 2 years, and then every 3 to 6 months. Results: A total of 314 patients with complete medical recorders and routinely monitoring BCR-ABL1 mRNA transcript data of each molecular response milestone were enrolled. Patients' characteristics are summarized in Table 1. The median follow-up time was 54 months (14 to 146 months). The 5-year cumulative rate of MMR, MR 4 and MR 4.5 with TKI treatment were 80%, 48.1%, and 38.4%, respectively. The results of the ROC analysis showed that a 3-month BCR-ABL1 mRNA transcript level of 4.94% correlated well with the 24-month DMR. The sensitivity and specificity of its predictive function were 82.8% (95% CI, 73.6-89.8) and 66.97% (95% CI, 60.3-73.1), respectively. So, we adopted BCR-ABL1 mRNA transcript level ≤4.94% at 3 months as the optimal threshold for predicting 24-month DMR. To reveal the cumulative incidence (CI) of 12-month MMR, 24-month MR 4 and MR 4.5 at different thresholds of BCR-ABL1 mRNA transcript levels at 3 months. Patients were divided into 3 groups according to the BCR-ABL1 mRNA transcript levels, group I <5% (n=150, 47.7%), group II 5% to 10% (n=36, 11.5%), group III >10% (n=128, 40.8%). Patients with BCR-ABL1 mRNA transcript levels <5% at 3 months after TKI initiation are more likely to achieve DMR than the other two groups and take less time to achieve DMR. Patients of Group I with 12-month MMR and 24-month MR 4 were significantly higher than the other two groups, with 66.7% vs 30.6% or 8.6% and 50% vs 16.1% or 7% (P<0.001), respectively. And group II was compared with group III. The cumulative incidence of MMR, MR 4 and MR 4.5 was also significantly higher in Group I than in the other two groups (Fig.1). The survival outcome of patients with BCR-ABL1 transcript levels <5% at 3 months had significantly superior compared with those with BCR-ABL1 transcript levels ≥5%: the 5-year EFS， PFS and OS were 88.6% vs 86.4% (P=0.037), 100% vs 95.7% (P=0.011) and 100% vs 95% (P=0.014)， respectively (Fig. 1). Conclusion: BCR-ABL1 mRNA transcript levels <5% at 3 months is a new landmark EMR (EMR <5%) which can predict 24-month DMR for patients with TKI treatment. EMR <5% may be used to guide the clinical timely switching of TKI or treatment and facilitate the implementation of TFR.

Distinct Circulating Genomic Features of Classical Hodgkin Lymphoma of Older Adults

Introduction: Despite significant progress in curing younger patients with classical Hodgkin lymphoma (cHL), older patients continue to have substantially inferior outcomes. The bimodal distribution of age at cHL diagnosis has suggested distinct underlying pathogenesis in older adults. For example, among older patients where EBV+ disease is more prevalent, EBV+ status is associated with worse outcomes, unlike younger patients where it confers more favorable prognosis (Keegan, JCO 2005). The reasons for this disparity remain enigmatic. To address these challenges, we used circulating tumor DNA (ctDNA) profiling, enabling noninvasive genotyping, risk stratification, and classification into distinct molecular subtypes (Spina, Blood 2018; Alig, ASH 2022). We leveraged several non-invasive techniques to systematically characterize the genomic peculiarities of elderly cHL patients distinguishing them from younger counterparts, with special attention to EBV status. Methods: We comprehensively profiled newly diagnosed cHL patients from 3 prospective clinical trials: LYSA-PVAB (NCT02414568) for subjects ≥60 years (Ghesquières, ASH 2019), AHL2011 (NCT01358747) for patients aged 16-59 years with advanced cHL, and BIO-LYMPH (NCT04417803) for patients ≥18 years. We used age ≥60 as a threshold for stratification of older versus younger patients, a common cutoff in clinical trials. We identified somatic single nucleotide variants using CAPP-Seq (Newman et al, Nature Biotech 2016); and analyzed copy number alterations with CANARy (Chabon, Nature 2020). Patients were categorized into high vs low pretreatment ctDNA levels using a predefined threshold (2.5 log hGE/mL; Kurtz, JCO 2018). We determined EBV status using EBER and/or LMP1 staining of FFPE tumor tissue or plasma EBV levels (>32 copies/mL) by VirCAPP-Seq (Garofalo, ASH 2022). Results: A total of 215 newly diagnosed cHL patients were evaluable, with a median age of 51 years, and 35% being older (≥60 years). In this cohort, 82% had advanced stage disease, 68% had high IPS (≥3), and 57% had extra nodal involvement. At 4-year follow-up, OS and PFS were 84% and 74%, respectively. At presentation, older patients (≥60y) had more advanced stage (93% vs 73%, p<0.001), higher IPS (78% vs 61%, p<0.001), and greater EBV+ prevalence (63% vs 36%, p<0.001). Older patients also experienced significantly more relapses (39% vs 17%, p<0.001). and mortality (29% vs 6%, p<0.001). The median pre-treatment ctDNA level was 982 hGE/mL, but not significantly different in older vs younger patients (p=0.28). Higher ctDNA levels were positively associated with risk-associated features including B symptoms (p=0.01), IPS (p<0.001), bulky disease (p=0.04), extra nodal disease (p=0.02) and correlated with TMTV (R=0.47, p<.001). Older patients had significantly fewer somatic mutations than younger counterparts (Median 107 vs 192 SNVs within targeted genomic regions, p<0.001; Fig. 1A top); among older patients, EBV+ cases had even fewer mutations than EBV- counterparts (Median 83 vs 142 SNVs, p=0.05). Older cHL cases harbored significantly more BCL2 mutations and recurrent copy number anomalies, but had significantly fewer mutations in STAT6, ITPKB, B2M, GNA13, PAX5 and XPO1 among others(all p<0.05 Fig. 1A bottom). The H2 genomic subtype prevalence, characterized by genomic instability as well as mutations in TP53, KMT2D, and BCL2 (Alig et al, ICML 2023), was higher among older patients (56%) than younger patients (21%) (p=0.01). Older H2 cHL showed no significant difference in EBV+ status compared to H1 counterparts (p=0.9). In older patients, multivariate Cox regression (including EBV status, ctDNA, and IPS) identified EBV+ status (HR=2.2, p=0.02) as an independent predictor of worse PFS and DFS outcomes (HR=2.5, p=0.02 and HR=2.7, p=0.04). When older cHL patients were stratified by baseline ctDNA level and EBV status, high-risk cases (EBV+ and ctDNA High) had particularly poor outcomes in terms of both PFS and DFS ( Fig. 1B). Conclusion: Older cHL patients exhibit unique genomic characteristics compared to younger counterparts, including more prevalent H2 tumor genetic subtype and EBV positivity. Identifying of a high-risk subgroup of older cHL underscores the importance of ctDNA levels and EBV status. We envision future trials of personalized biomarker driven treatment strategies could therapeutically target this risk, including by PD1 blockade.