5-year PFS Research Articles

Clinical Observation of Camrelizumab (CAM) Combined with Bendamustine and Gemcitabine (BeGe) in Relapsed/Refractory Classical Hodgkin Lymphoma (cHL): A Phase II Trial

Background The cure rate of classical Hodgkin's lymphoma (cHL) is more than 80%. However, 20% or so of cHL patients have refractory or recurring disease, making clinical treatment complex and challenging. Currently, the standard treatment for patients with r/r-cHL is high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDCT/ASCT). However, the complete response rate of traditional salvage chemotherapy is not ideal, which prevents some patients from receiving stem cell transplantation. In recent years, with the application of new drugs such as PD1 inhibitors, the efficacy of R/R cHL has been further improved. we designed a prospective, single-arm, multi-center trial to evaluate the efficacy and safety of PD-1 antibody camrelizumab combined with bendamustine and gemcitabine（BeGe）in patients with relapsed or refractory (r/r) classical Hodgkin Lymphoma (cHL). Methods This research is a phase 2 exploratory, open-label, multi-center study. Key inclusion criteria include age≥18 and ≤75, ECOG<2, R/R cHL who had received at least first-line chemotherapy, at least one measurable lesion per Lugano criteria 2014, and preparing to receive autologous stem cell transplantation (ASCT). Patients were treated with camrelizumab (CAM, 200 mg IV, day 1 q3w) combined with bendamustine （90mg/m 2, IV, day 2 and Day3) and gemcitabine (1000 mg/m 2 day 1 and day4) for 2 cycles. Patients with complete response (CR) underwent autologous hematopoietic stem cell transplantation after high-dose chemotherapy (HDT/ASCT). Patients who did not achieve CR underwent HDT/ASCT if CR was attained after two additional cycles of CAM plus BeGe. 1-2 cycles of CAM monotherapy were permitted for individuals who were waiting more than 4 weeks for ASCT. The primary endpoint was the proport ion of patients who achieved PET-CT-confirmed complete response (CR) according to Lugano 2014 criteria. Results 17 individuals were enrolled between February 2022 and May 2023, including 5 relapsed and 12 refractory patients. 14 (82.4%) of the enrolled patients were younger than 60 years old, with a median age of 37 years (range: 20-62) and 76.5% male. 12 patients had received first-line prior therapy, and 5 patients had received second-line therapy or more. After 2 cycles CAM plus BeGe, Overall response rate (ORR) was 94.0% (16/17) with CR rate of 64.7% (11/17) and PR rate of 29.4% (5/17). Only one patient withdrew from the study because to progressive disease (PD). 4 patients who achieved PR received 2 additional cycles of CAM plus BeGe, and 2 patients achieved CR. Up to now, autologous hematopoietic stem cell transplantation has been carried out in 7 patients, with stem cell being collected from 5 patients after 2 cycles and 2 patients after 4 cycles. With a cutoff date of June 10, 2023, the 1-year (progression-free survival) PFS rate was 86.3% and the 1-year (overall survival) OS rate was 94.1%. One patient experienced grade 3 pancreatitis. Grade 1-2 AE occurred in 9 patients, and common AEs included pruritus(4/17), pyrexia(4/17), bone marrow suppression(2/17), nausea(1/17), diarrhea(1/17), mild reactive cutaneous capillary endothelial proliferation(RCCEP, 1/17). No grade 4 or above AEs occurred. Conclusion It is well known that refractory cases are more difficult to treat and have a worse prognosis than relapsed cases. Despite the preponderance of refractory cases in this study, the response was excellent. Therefore, Camrelizumab combined with BeGe chemotherapy patients shows encouraging clinical efficacy and safety in R/R HL, and has no significant effect on stem cell collection, which is worthy of further study.

Sequential Conditioning Does Not Improve Outcomes of Allogeneic Stemcell Transplantation in CMML Patients

Background: Allogeneic stem cell transplantation (SCT) is potentially curative therapy for patients with CMML. Data on optimal allo-SCT conditioning in CMML Patients is scarce. Methods: This retrospective study from the Department of Stem Cell Transplantation at the University Medical Center Hamburg, Germany, compared allo-SCT outcomes in CMML patients across three conditioning regimes: Thiotepa-Busulfan (TB), Sequential FLAMSA-Busulfan Fludarabine (FLAMSA-FB), and Treosulfan-Fludarabine (Treo-Flu). TB consisted of Thiotapa ( 5mg/Kg; a total dose of 10mg/Kg) on day -6 and -5 and Busulfan (3.2mg/Kg; total dose 6.4mg/Kg or 9.6mg/Kg) on days -4 and -3 or -4 to -2. FLAMSA-FB regimen consists of fludarabine (30 mg/m 2 ; total dose 120 mg/m 2 ), amsacrine (100 mg/m 2 ; total dose 400 mg/m 2 ), and cytarabine (1 g/m 2 ; total dose 4 g/m 2 ) therapy from days -11 to minus -8, followed by a three-day interval without therapy and Busulfan from day -4 to -2 with a total dose of 6.4mg/Kg and Fludarabine on day -4 and -3 (30 mg/m 2, total dose 60mg/m 2 ).Treo-Flu regimen consisted of Treosulfan (12 g/m 2 , total dose 36 mg/m 2 ) on days-6 to -4 and fludarabine (30 mg/m 2 ; total dose 150 mg/m 2 ) on days -6 to -2. Results Sixty-nine consecutive patients with CMML who underwent allo-SCT between the years 2006-2022. Twenty-two received TB, 27 received FLAMSA-FB, and 20 received Treo-Flu conditioning. Transplant sources included matched related donors (MRD, 8 patients), mismatched related donors (MMRD, 8 from TB), matched unrelated donors (MUD, 31), and mismatched unrelated donors (MMUD, 23) with significant group variations (p<0.001). Most Patients received ATLG for GVHD prophylaxis (TB 68%, FLAMSA-FB 93%, Treo-Flu 85%, p=0.08). Regarding CPSS-mol scores, the TB group exhibited a significantly higher proportion of high (46%) and intermediate-2 scores (32%) than FLAMSA-FB (11% high, 7% intermediate-2) and Treo-Flu (40% high, 20% intermediate-2) (p=0.001). One TB patient experienced primary graft failure, but engraftment times were comparable across groups. Although not statistically significant (p=0.07), the TB group showed a trend towards improved 3-year OS rates (84%) compared to FLAMSA-FB (37%) and Treo-Flu (49%). The TB group also displayed significantly higher 3-year PFS rates (79%) compared to FLAMSA-FB and Treo-Flu (both 30%), (p=0.03). (Figure 1) No significant differences were observed in 3-year non-relapse mortality (NRM) across the TB (17%), FLAMSA-FB (30%), and Treo-Flu (26%) groups (p=0.7). Interestingly, no TB patients relapsed at 3 years, contrasting with the FLAMSA-FB (41%) and Treo-Flu groups (43%, p=0.02). Lastly, cumulative incidences of acute GVHD grade II-IV (TB 41%, FLAMSA-FB 35%, Treo-Flu 30%, p=0.75) and all-grade chronic GVHD (TB 50%, FLAMSA-FB 65%, Treo-Flu 40%, p=0.35) were similar across groups. Conclusion Our study suggests that sequential conditioning with FLAMSA-FB does not improve Transplant outcomes in patients undergoing allo-SCT for CMML.

A Retrospective Comparison of Allogenic and Autologous Hematopoietic Stem Cell Transplantation in Patients with T-Cell Lymphoblastic Lymphoma

Background: T-cell lymphoblastic lymphoma (T-LBL) is a rare type of non-Hodgkin's lymphoma accounting for 1%~2% of non-Hodgkin's lymphoma. T-cell lymphoblastic lymphoma is typically found in children and young adults, frequently affecting the mediastinum and bone marrow. It has a poor prognosis and develops quickly. It is anticipated that hematopoietic stem cell transplantation will significantly enhance the prognosis. We conducted a retrospective single center analysis aiming to compare the survival outcomes of autologous and allogeneic hematopoietic stem cell transplantation in patients with T-cell lymphoblastic lymphoma. Methods: From our center's database, we track down 92 individuals who underwent T-LBL transplantation between August 2011 and June 2022, including 77 individuals who got allogeneic hematopoietic stem cell transplants and 15 patients who underwent autologous hematopoietic stem cell transplants. Results：For the baseline characteristics of patients,there were significant differences in IPNHLSS staging, bone marrow involvement, IPI score and pre transplant status between Auto-HSCT group and Allo HSCT group.Group allo-HSCT had a higher proportion of bone marrow involvement (57.1% vs. 26.7%,p=0.031), a higher proportion of IPNHLSS staging as IV (57.1% vs. 26.7%,p=0.001) and a lower proportion of CR1 pre transplantations (51.9% vs. 86.7%,p=0.080). Figure 1 had shown the survival between auto-HSCT group and allo-HSCT group.Among the 15 patients who received auto-HSCT, 2 patients received allogeneic transplantation after relapse, 1 patient died after 3.1 months of survival after secondary transplantation, and 1 patient still survived after secondary transplantation.The 3-year OS rate of auto-HSCT group was 87.7%, while the 3-year OS rate of allo-HSCT group was 65.0%（P=0.086).The 3-year PFS rate of auto-HSCT group was 74.0%, while the 3-year PFS rate of allo-HSCT patients was 73.3%（P=0.95). The 3-year NRM rate of auto-HSCT group was 0%, while the 3-year NRM rate of allo-HSCT group was 9.9%（P=0.127). The 3-year CIR rate of auto-HSCT group was 21.0%, while the 3-year NRM rate of allo-HSCT group was 25.3%（P=0.514). Conclusion: Hematopoietic stem cell transplantation can significantly improve the prognosis of patients with T-cell lymphoblastic lymphoma. In our study, patients with T-cell lymphoblastic lymphomareceiving autologous hematopoietic stem cell transplantation and those receiving allogeneic hematopoietic stem cell transplantation have distinct baseline data, hence their survival rates also differ.

Post-Allograft Romidepsin Maintenance Mitigates Relapse Risk and Stimulates the Graft-Versus-Malignancy Effect through Enhanced NK-Cell Cytotoxicity in Patients with T-Cell Malignancies: Final Results of a Phase I/II Trial

Background: For patients with high risk, and relapsed/refractory T-cell malignancies allogeneic stem cell transplant (allo-SCT) is the only available potentially curative therapy. The efficacy of allo-SCT is limited in this population by high rates of relapse, with rates up to 55-60% post-allo-SCT. We designed a phase I/II trial, evaluating the combination of the histone deacetylases inhibitor romidepsin (rom) with busulfan/fludarabine (BuFlu) conditioning, followed by romidepsin maintenance (m-rom) in patients receiving allo-SCT for T-cell malignancies (NCT02512497). Here we present final clinical results of this therapeutic approach, including an evaluation of the stimulatory effects of m-rom on the graft-versus-malignancy effect through NK-cells post-allo-SCT. Methods: This was a phase I/II clinical trial. Eligible patients had: a diagnosis of T-cell leukemia (including T-acute lymphoblastic leukemia) or T-cell lymphoma (TCL, cutaneous or peripheral) in at least a partial remission requiring an allo-SCT, <70 years of age, with a matched sibling/unrelated donor. Patients received myeloablative (20K) or reduced intensity (16K) BuFlu with rom, followed by standard tacrolimus/methotrexate GVHD prophylaxis and anti-thymocyte globulin for unrelated donors (MUD). An expansion cohort of up to 30 patients (total) was included. M-rom was initiated between day +28 and +100 for 1 year (2 nd year optional), with built in dose reductions for toxicity. An efficacy endpoint of 20% reduction in relapse risk at 1-year in the whole cohort or any individual disease cohort was set based upon historical/CIBMTR (Center for Blood and Marrow Transplant Research) controls was pre-specified. The effect of m-rom on NK-cell cytotoxicity was assessed on samples taken pre-transplant, and 1, 3, 6, 12 months post allo-SCT. NK cytotoxicity was assessed by isolating mononuclear cells from patient samples at each timepoint, comparing those on m-rom (n=13) versus those who did BuFlu controls who did not receive m-rom (n=16). Cells were targeted against K562 targets using the calcein-AM assay. K-M and Fine-Gray models were used to estimate PFS, OS, and cumulative incidence, and compare survival across groups. Results: 28 patients were enrolled on this trial (Table). With a median follow-up time of 15 months, the median OS is 3.3 years (95% CI: 0.85-not reached), with a 1 and 3 year OS probability of 68% and 54%. The median PFS is 2.3 years (95% CI: 0.6-not reached), with 1 and 3-year PFS of 61% and 41%. Cumulative incidence (CI) of NRM at day 100 and 1 year were 14.3% and 21.4%. CI of grade II-IV aGHVD and extensive cGVHD were 46.4% and 38%. The CI of relapse (CIR) was 18.1% at 1 year and 33% at 3 -years. There was no difference between PFS among patients with MRD versus those without MRD prior to transplant (p=0.43). The CIR of patients with TCL was 9.3% at 1 and 3 years, whereas the CIR of patients with leukemia was 25% at 1 year and 48% at 3 years. No patients with PTCL relapsed, 1/2 patients with CTCL relapsed, and 4/6 patients with T-PLL are alive, disease free. Pre-specified general CIR was 55% for all patients. With an overall CIR of 18% at 1 year, and 33% at 3-years, this trial met its pre-specified endpoint of decreasing relapse by 20% at 1-year, and performed well compared to published CIBMTR control populations. Matched propensity score analysis across disease subsets with CIBMTR controls will be presented. 18/28 (64%) of patients received m-rom with a median number of 13 cycles (range 1-47). 8 patients experienced grade 3/4 adverse events (AE), and 1 patient discontinued m-rom due to toxicity, unlikely related to romidepsin (loss of CD3 chimerism). When NK-cytotoxicity was assessed between the two groups after starting maintenance, NK-cytotoxicity in the m-rom group was significantly higher than in those without m-rom (p<0.0001) (Figure). Conclusions: BuFluRom with m-rom is effective at decreasing relapse in patients with T-cell malignancies, with 1-year CI relapse below expected relapse rates for this set of diseases, meeting the pre-specified efficacy endpoint. NK-cell cytotoxicity data in a large sample set of trial patients demonstrates that m-rom enhances NK-cell cytotoxicity post allo-SCT, augmenting the GVL effect and likely accounting for at a minimum, some of the decrease in relapse seen on this trial. M-rom should be considered a new option post allo-SCT to mitigate relapse in patients with T-cell malignancies.

A Phase II Study of Flumatinib with Chemotherapy for Newly Diagnosed BCR::ABL1-Positive Acute Lymphoblastic Leukemia in Adults: Updated Results from RJ-ALL2020.2A Trial

Background The introduction of the second-generation TKIs further improved outcomes in BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). Flumatinib is a novel second-generation TKI approved in China in 2019. It has shown better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL. Herein, we report the updated results of the RJ-ALL2020.2A trial, which is the first reported registered clinical trial of flumatinib in adult BCR::ABL1+ ALL last year. The enrollment will be completed at the end of Aug. 2023. Methods In this prospective phase II study, patient (pt) eligibility mainly includes: 18≤age＜65 years; newly diagnosed BCR::ABL+ ALL; with adequate organ function. Once the diagnosis is confirmed, the combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is given promptly. Allo-HSCT is recommended for all eligible pts. Blinatumomab is allowed to administer for MRD clearance before allo-HSCT. All pts receive central nervous system (CNS) prophylaxis once achieving remission. The choice of subsequent salvage treatments is based on the discretion of physicians. Multiparameter flow cytometry (minimal residual disease[MRD]<10 -4) and RT-qPCR (BCR-ABL1 transcript<10 -5) are used to monitor MRD. The primary endpoints are MRD clearance, PFS, and OS. (Clinical Trial Registration Number: ChiCTR2100042248) Results From Dec. 2020 to Jun. 2023, 81 adult pts with de novo BCR::ABL1+ ALL were enrolled. Seventy-eight pts were included in the efficacy and safety assessment (3 were excluded due to the short duration of treatment), and 76 were available for survival analysis (2 withdrew). Median age was 42 years (range, 18-63). Median WBC count at diagnosis was 38.7×10 9/L (0.6-675.3). Four pts had primary CNS leukemia (Table 1). Among 78 pts, 75 (96.2%) achieved CR/CRi at the end of induction, and 78 (100%) achieved CR/CRi at any time. No early death occurred during the induction course. MRD flow negative rates were 67.1% (51/76) and 79.7% (55/69), while the CMR rates were 31.1% (23/74) and 52.2% (36/69) at the end of induction and 3 months, respectively. With a median follow-up time of 16.2 months (range, 1.8-29.2), the estimated 2-year PFS and OS rates were 64.8% and 81.3% (Figure 1). Among the 69 survived pts, 61 were in continuous remission, and 8 were relapsed (4 had CNS involvement). Among 7 deaths, 6 died of disease progression (4 had CNS involvement), and 1 of pulmonary infection post-HSCT. There was a survival superiority in pts who achieved MRD flow negativity (PFS: p=0.091, OS: p=0.005) or CMR (PFS: p=0.055; OS: p=0.033) at 3 months. With a median time of 6.4 months (range, 1.6-10.3) from diagnosis, 46 pts (median age of 39 years [range, 20-60]) received allo-HSCT with 45 pts in CR1. The MRD flow negativity and CMR rates were 82.2% (37/45) and 70.5% (31/44) before HSCT, respectively. PFS and OS significantly improved in patients who underwent HSCT (PFS: p<0.001, OS: p=0.012). In multivariate analysis for PFS and OS, MRD flow negativity at 3 months (PFS: HR: 0.129, p=0.016; OS: HR: 0.151, p=0.029) and allo-HSCT (PFS: HR: 0.247, p=0.036; OS: HR: 0.176, p=0.042) still had a significant effect on PFS and OS as protective factors. When including CMR as a variable, CMR at 3 months (PFS: HR: 0.221, p=0.02; OS: HR: 0.115, p=0.054) and allo-HSCT (PFS: HR: 0.169, p=0.01; OS: HR: 0.139, p=0.021) had the similar impact on survival. Among 75 pts evaluable for ABL1 mutations, 24 (32%) pts were mutated, and T315I was the most frequently identified (75%). Pts with T315I mutation showed a poorer outcome than non-T315I mutation (PFS: p<0.001, OS: p=0.01). Meanwhile, the safety profiles of the flumatinib-based therapy were acceptable. Non-hematological AEs were mostly G1-2, which were reversible rapidly after symptomatic management. Most of the G3-4 AEs were hematological, possibly related to chemotherapy. No permanent discontinuation or death related to flumatinib was observed. Conclusion This prospective study further confirmed the efficacy and safety of the promising second-generation TKI flumatinib combined with chemotherapy in newly-diagnosed Chinese adult pts with BCR::ABL1+ ALL. Achieving MRD flow negativity or CMR at 3 months and bridging allo-HSCT could further improve survival. The long-term follow-up data will be disclosed soon.

Real-World Outcomes in Patients with Transformed Follicular Lymphoma Treated with CD19-Targeting CAR-T Therapy

INTRODUCTION. CD19-targeting CAR-T cell therapy has changed the treatment landscape of refractory/relapsed large B cell lymphoma, including transformed from FL (tFL). Axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel) are now FDA-approved for the treatment of tFL, but limited data are available on their clinical activity in patients (pts) with tFL since outcomes in those pts were not separately reported in registrational studies. Here, we report a single center's experience with CD19-directed CAR-T cell therapy in pts with tFL. METHODS. We performed a retrospective analysis of 54 pts with tFL treated with CAR-T cell therapy from January 2018 to December 2022. Pathological evidence of histologic transformation (HT) was confirmed. The main clinical-biological characteristics of the pts were extracted from the electronic medical records. Cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT guidelines. Progression-free (PFS) and overall survival (OS) were measured from the time of CAR-T cell infusion; PFS events were death, relapse, and disease progression. RESULTS. Within our cohort of patients with tFL, the median age was 67 years (range 42-81), 65% were male and 77% had stage III-IV disease. Eight of the pts (15%) had an ECOG Performance Status (ECOG-PS) ≥2. Median time to transformation was 27 months from original FL diagnosis (range 0 to 223), including 6 cases with composite lymphoma (FL + aggressive histology) and 4 with synchronous transformation. Twenty percent presented with high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements. Using Hans' algorithm, 85% (44/52) were identified as a germinal center B-cell origin (GCB). In 22 cases, targeted sequencing using the MSK-IMPACT panel was performed at the time of HT or prior to CAR-T. TP53 mutation/deletion was present in 50% of the cases (Figure 1). Pts received a median of 3 (range 1-9) prior lines of therapy including those for FL, and 9 pts (17%) had undergone prior autologous stem cell transplantation (SCT). Thirty-four pts (63%) were refractory to the last therapy, including 29 pts (53.7%) with primary refractory disease after HT. Forty-one pts (76%) received bridging therapy. Seventy-two percent of pts received axi-cel, 19% tisa-cel, and 9% liso-cel. CRS of any grade was seen in 43 (80%) pts with grade >3 in 3 (6%). Neurologic toxicity of any grade was observed in 20 (37%) pts with grade >3 in 7 (13%). The median duration of follow-up was 26.2 months. The overall response rate was 87%, including 67% complete response (CR). The median response duration (DOR) was 11 months, with a 2-year DOR of 42% (95% CI: 28-61%). Objective responses were achieved in pts with high-risk features such as HGBCL, TP53 mutation, and chemotherapy-refractory disease. Twenty-nine pts experienced relapse/progression during follow-up, with a median PFS for the entire cohort of 9.8 months and a 2-year PFS of 40% (95% CI: 28.3-56.3%) (Figure 2). Refractory disease after HT and high LDH serum levels were associated with a significantly lower PFS (median PFS not reached vs. 6.4 months, P=0.031; 24.4 vs. 3.2 months, P=0.003 respectively). Notably, all pts who achieved PR eventually progressed. In 23 pts with relapse, a biopsy was obtained, showing DLBCL or HGBCL morphology in all instances. Interestingly, all relapses occurred during the first 24 months. Twenty-six pts received salvage therapy after CAR-T progression, with a median of 1 line (range 1-7). Out of these, eight (31%) pts achieved a CR and went to allogenic SCT as a consolidative strategy. Twenty-two pts died during follow-up, 19 due to progression and 3 of non-lymphoma causes, including 2 of COVID-19 infection. The median OS was 31 months, and the 2-year OS rate was 57% (95% CI: 44.3-73.8%) (Figure 2). Median OS was not reached among the 36 pts who achieved a complete response. CONCLUSIONS. CD19-targeting CAR-T cell therapy is effective for pts with relapsed/refractory tFL, including patients with characteristics of poor prognosis, with efficacy and toxicity profiles comparable to that observed in previous DLBCL studies. Unfortunately, pts who relapse post-CAR-T therapy have limited effective therapeutic options available, and this currently remains an unmet medical need within the field.

Addition of Acalabrutinib to Lenalidomide and Rituximab Induces High Complete Response Rates in Patients with Previously Untreated Follicular Lymphoma: Results of a Phase II Study

Background. We previously reported pro-tumoral macrophages may be associated with resistance to lenalidomide and rituximab (R 2) treatment in follicular lymphoma (FL) ( Marques-Piubelli, Blood Adv 2022). As pre-clinical studies suggest that BTK inhibition can mitigate the crosstalk between monocyte/macrophages and FL B cells, we hypothesized that acalabrutinib, a specific BTK inhibitor, may synergize with R 2 without increasing toxicity. In agreement with this, the combination of acalabrutinib and R 2 (aR 2) was shown to be safe and effective in patients with relapsed FL ( Strati P et al, ASH 2022). Here, we investigated the safety and efficacy of aR 2 in previously untreated FL patients and analyzed the biological effects of this combination on peripheral blood immune cells. Methods. This phase 2 single arm study (NCT04404088) was conducted between 09/2020 and 09/2021 (data cutoff 06/2023). Adult patients with previously untreated FL, grades 1 to 3A, stage 3-4, and meeting indication for treatment per GELF criteria were included. Treatment consisted of acalabrutinib lead-in at 100 mg PO twice a day for one 28-day cycle and continued for total of 13 cycles, lenalidomide 20 mg PO daily on days 1-21, during cycle 2-13, and rituximab 375 mg/m 2 IV weekly during cycle 2, and on day 1 of cycle 3-13. The primary endpoint was best complete response (CR) rate per Lugano 2014 criteria. Bulk RNA sequencing with deconvolution to characterize circulating immune cells was performed on peripheral blood collected at baseline, and on day 1 of cycles 2 and 6. Results. We enrolled and treated 24 patients. Baseline characteristics are shown in the Table. Median number of cycles was 13 (range, 6-13) and 15 (62.5%) patients experienced a cycle delay, due to COVID19 in 11 (46%) cases; 6 (25%) patients required dose reduction of lenalidomide, but none discontinued, and 2 (8%) required dose reduction of acalabrutinib and 1 discontinued. The most common (>5% of patients) grade 3-4 adverse events were neutropenia (58%), liver function test elevation (17%), infection (12.5%; 2 out of 3 related to COVID19), anemia (8%) and skin rash (8%). Best ORR was 100%, best CR rate was 92%, and median time to CR was 3 months ( Figure). After a median follow-up of 26.8 months (95% CI 24.6-29.6 months), 6 (25%) patients had disease progression, including 2 who transformed at 5 and 7 months. The 2-year PFS rate was 79.2% (95% CI, 64.5-97.2%). At data cutoff, 2 patients have died, 1 due to COVID19 (while in CR, at 14 months) and 1 due to transformed lymphoma (at 10 months). The 2-year OS rate was 91.7% (95% CI, 81.3-100%). While the frequency of circulating immune cells were unchanged after single agent acalabrutinib, its use associated with a significant decrease in the expression of VMO1 (FDR 0.001), a gene encoding for a protein expressed on extra-cellular exosomes derived from non-classical monocytes, and a significant increase in gene signatures of monocyte proliferation (p=0.01), TNF response (p=0.01), anti-viral (p=0.006) and anti-tumoral activity (p=0.009), consistent with the expected effect of BTK inhibition in monocytes. After 5 cycles of aR 2, we observed a decrease in the frequency of circulating B cells (p=0.003) and regulatory NK cells (p=0.01), and an increase in the frequency of circulating naive T cells (p=0.004), CD4+ T cells (p=0.005) and classical monocytes (p=0.003). Conclusion. Our results indicate that the addition of acalabrutinib to R 2 is a safe and effective frontline non-chemotherapy regimen for FL patients, resulting in high CR rates, and induces favorable biological changes in multiple circulating immune cells. Since CRs occurred early, the study has been amended to include 26 additional patients who will be treated with only 6 cycles of aR2.

Zanubrutinib, Lenalidomide Combined with R-CHOP As the Frontline Treatment for Mantle Cell Lymphoma

Objectives Mantle cell lymphoma (MCL) has poor prognosis with existing available therapies. Zanubrutinib, a novel BTK inhibitor, has shown promising outcomes in relapsed/refractory MCL. The aim of this retrospective study was to evaluate the efficacy and safety of zanubrutinib combined with R2-CHOP (lenalidomide, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in newly diagnosed MCL. Methods We retrospectively analyzed newly diagnosed MCL between September 2020, to March 2023 in a single-center in China. All patients received zanubrutinib 160 mg twice daily, lenalidomide 25 mg daily (days 1 to day 14), rituximab 375 mg/m 2, cyclophosphamide 750 mg/m 2 (day 1), doxorubicin 50 mg/m 2 or liposome doxorubicin 40 mg (day 1), vincristine 1.4 mg/m 2 (day 1), and prednisone 100 mg (day 1 to day 5) every 3 weeks. After 4 cycles, autologous hematopoietic stem cell transplantation (ASCT) was performed according to the patient's condition. After 6 cycles of induction or ASCT, patients with an objective response (complete or partial response) continued to receive zanubrutinib twice daily plus rituximab maintenance therapy, administered every 12 weeks for up to 8 additional doses. All patients underwent CT or PET-CT scans to evaluate mid-term efficacy. After 6 cycles, PET-CT scans were evaluated for patients whose mid-term efficacy did not achieve complete metabolic response (CMR). Results All of 5 patients treated with ZR2-CHOP were enrolled. The median age was 50 years (range: 44-66 years), 3 patients were females, 2 patients were males. 3 patients were classical MCL, 1 patient was pleomorphic MCL, and 1 patient was blastoid-variant MCL. The overall response rate was 100% (5 of 5), and all of them achieved CMR (Figure 1). Three patients achieved CMR after 4 cycles received ASCT, two received 6 cycles. At the mid-term evaluation after 4 cycles, 4 patients achieved CMR, 1 patient achieved PR but achieved CMR after 6 cycles. At data cutoff (22 March 2023), the median follow-up time was 26.1 (range, 12.5-32.4) months. The median PFS and OS rates were not reached. The 2-year PFS rate and the 2-year OS rates were both 100% (Figure 2). The most common grade 3/4 adverse events were neutropenia (60%) and thrombocytopenia (40%), all of which were controllable and resolved. The results of WES analysis showed that the most common gene mutations were KMT2D (frequency, 60%) and DDR2 (frequency, 40%). ctDNA was dynamically detected in four patients. Matched analysis of WES and ctDNA showed that gene mutations detected by these two methods were highly consistent, with 3 out of 4 patients being consistent. Among them, one showed negative ctDNA before and after treatment, while the other three patients indicated a decreasing trend in ctDNA mutation rate after 4 or 6 cycles, including a 50% decline or a change from baseline to negative. Conclusions: ZR2-CHOP showed promising preliminary efficacy and acceptable safety in previously untreated patients with MCL.

Primary Analysis and Results of Bendamustine, Rituximab, and Venetoclax (BR-VEN) for Initial Treatment of Mantle Cell Lymphoma in Subjects over 60 Years of Age (PrE0405)

Background Mantle cell lymphoma (MCL) is an incurable form of aggressive non-Hodgkin lymphoma. Treatment choice at diagnosis is based on tolerability of cytarabine and high-dose chemotherapy. With a median age of 60-70 years, many patients are ineligible for aggressive treatment. Bendamustine and rituximab (BR) is a reasonable treatment option (E1411, Smith MR et al. ASH 2022) for this patient population and venetoclax (VEN) has shown pre-clinical evidence of synergy with chemoimmunotherapy. PrECOG 0405 was designed to evaluate the addition of VEN to BR in previously untreated patients with MCL aged over 60 years. Methods Eligible patients included those that were previously untreated and diagnosed with MCL as defined as the presence of t(11;14) by FISH or cyclin D1 expression by IHC. Patients must have been at least 60 years of age or older on D1C1 of therapy with a good performance status (ECOG 0-2). Adequate marrow and organ function was required, specifically a creatinine clearance of ≥ 40 mL/min. Treatment administration is summarized in Figure 1. Dose of bendamustine was either 90mg/m 2 D1&2; or, for subjects over the age of 75 years, 70mg/m 2 was allowed per investigator discretion. VEN was dose escalated during Cycle 1 to 200mg. At the time of C2, BR was repeated and VEN was also escalated to 400mg. With C2-6, VEN 400mg PO daily was given D1-10 only. Primary endpoint was PET-negative complete response (CR) rate at end of treatment (EOT) by Lugano Criteria. A negative bone marrow biopsy was required to confirm CR if involved at screening. Minimal residual disease (MRD) by next-generation sequencing was performed at the EOT. Maintenance rituximab was encouraged per investigator discretion. This was a single arm study with an original accrual goal of 53 subjects to detect a 15% improvement in CR rate compared to historical data. However, due to slow study accrual during COVID pandemic and preliminary efficacy data from E1411 study, the statistical parameters were updated after 25 subjects had been accrued. The revised accrual goal was 33 patients to obtain 32 eligible and treated patients, which provided 81.8% statistical power to detect a 17% difference in CR rate (from 60% [E1411 data] to 77%) using an exact binomial test with a 1-sided alpha of 11.6%. This combination regimen will be considered promising if 23 or more (out of 32) patients attain CR. Results From January 2020 to March 2022, 33 subjects enrolled and were treated on study. Subject characteristics are listed in Table 1. Seven (21%) unique subjects were treated with 70mg/m 2 of bendamustine during induction cycles. Laboratory tumor lysis syndrome (TLS) was seen in 2/33 during C1 only; clinical TLS was not seen. Treatment was generally well tolerated with treatment-related adverse events (TRAE) of Grade ≥3 and occurring in >10% of subjects being neutropenia (n=5, 15%), thrombocytopenia (n=5, 15%) and lymphopenia (n=9, 27%). Other common non-hematologic TRAE of all grades were nausea/vomiting (n=26, 79%), diarrhea (n=10, 30%), and fatigue (n=17, 52%). There were 4 (12%) instances of COVID-19/COVID-19 pneumonia considered treatment related. Dose adjustments and delays for any drug occurred in 36% and 67% of subjects respectively. 22/33 (66.7%) subjects completed 6 cycles of BR-VEN. Maintenance rituximab was administered in 19/33 (57.6%) of subjects. Overall response rate was 97% (32/33) and PET-negative bone marrow biopsy confirmed CR Rate at EOT was 85% (28/33), achieving the primary endpoint (≥23 CRs). MRD at EOT is under analysis. With a median survival follow up of 21.5 months (mo), Median PFS and OS were not reached; estimated 2-year PFS and OS was 69.7% and 81.1% respectively. During follow up, there have been 6 deaths, 4 from COVID-19 (all in remission), one from influenza A (in remission), and one from disease progression (non-responding pt). There have been 2 other progression events who are alive. Conclusions BR-VEN was generally well-tolerated in this older patient population though GI toxicities were common. With a PET-negative CR rate of 85%, the combination is promising but longer follow-up is needed. There was a competing risk of death related to upper respiratory viruses identified, mostly COVID-19, as has been seen in other BR-based protocols during the COVID-19 pandemic. MRD analysis and survival data will be updated.

A Retrospective Study on Outcomes of Secondary CNS Lymphoma: Pattern of Relapse, Prognostic Factors, and Role of Consolidation Therapy

Introduction Secondary CNS lymphoma (SCNSL) remains a treatment challenge in patients (pts) with aggressive lymphoma. Outcome of SCNSL is poor. Pts are often treated with high dose Methotrexate (HD-MTX) based regimens followed by autologous stem cell transplant (auto SCT). However, the benefit of consolidation therapy is not well established. There is limited data on the treatments and outcomes of SCNSL. In this single institution study, we aim to analyze the role of consolidation therapy and potential prognostic factors of outcomes in SCNSL. Method All pts with a diagnosis SCNSL who presented to Moffitt Cancer Center, FL, USA between 2017 and 2022 were included. The hazard ratios (HRs) were evaluated in the univariate and multivariate analysis using the cox proportional hazard mode. All analyses were done using SAS 9.4. Results A total of 60 pts with SCNSL were identified. The median age was 63 years (range 26-83 years); 27 (45%) were female; 13 (21.7%) had Eastern cooperative oncology group performance status (ECOG) ≥2. Entire cohort was divided in 3 subgroups: pts with concurrent CNS involvement at the time of initial diagnosis with systemic lymphoma (Sys-CNS) [22 (36.7%)]; pts with isolated CNS relapse (R-SCNS) [30 (50.0%)]; and pts with simultaneous CNS and systemic relapse (R-Sys-CNS) [8 (13.3%)]. 31 (51.7%) pts had brain parenchymal involvement, 24 (40%) had leptomeningeal disease, 4 (6.7%) had both leptomeningeal and parenchymal involvement, and 1 (1.7%) had ocular disease. 58(96.6%) pts had diffuse large B cell lymphoma (DLBCL) histology; 9 (15%) had DLBCL with MYC and BCL2 rearrangement; 10 (16.7%) had DLBCL MYC and BCL2 expression. For induction therapy of SCNSL, 53 (88.3%) of pts received HD MTX-based chemotherapy; 2 (3.3%) received Bruton tyrosine kinase inhibitor (BTKi), and 5 (8.3%) with meningeal disease alone received IT chemotherapy and/or rituximab(R). Sys-CNS pts also received R-CHOP or DA-R-EPOCH while R-Sys-CNS pts received R-Polatuzumab or Polatuzumab-R-Bendamustine. 20 (33.3%) received consolidation either by WBRT [13 (21.7%)] or auto SCT [4 (6.7%)]; 3 (5.0%) proceeded with chimeric antigen receptor (CAR-T) therapy. The overall response rate (ORR) for entire cohort was 55.2% (34.5% complete response CR and 20.7% partial response PR). However, improved ORR and CR were observed with 14(73.68%) and 9 (47.37%) respectively in pts who received consolidation. ORR and CR for pts with Sys-CNS, R-SCNS, R-Sys-CNS were 13 (61.9%)/ 10 (47.6%), 14 (48.3%)/9 (31%) and 2 (25%)/ 2 (25%), respectively. After a median follow up of 33.6 months, median OS was 8.3 months with a 2-year survival probability of 33.8% (95% CI: 21.7-46.3%); the PFS was 6.5 months with a 2-year PFS probability of 32.9% (95% CI: 20.7-45.6%). Consolidation therapy with either auto SCT or WBRT had significant survival benefit. In this subgroup, median OS is not reached (NR) and the 2-year OS probability was 59.6% (95% CI: 32.9-78.7%); median PFS was 25.6 months and 2-year PFS probability was 53.3% (95% CI: 27.5-73.6%). After the first-line therapy for CNS disease, 21(35%) pts experienced relapsed. However, relapse rate in consolidation group [7 (36.8%)] was almost similar to those who did not receive consolidation [14 (34.2%)] (table 1). 39 (65%) pts died; 29 (48.33%) from disease progression, 3 (5%) from therapy related side effect and 7(11.7%) from other causes. In the univariate analysis, ECOG PS ≥2 [HR 3.60 (CI:1.80-7.20), p<0.001], lack of consolidation therapy [2.45 (CI:1.12-5.36), p=0.024], <3 cycles of HD-MTX containing regimen [2.85 (CI: 1.47-5.520), p=0.002] and double hit lymphoma [2.27 (CI: 1.02-5.06), p=0.045] were associated with worse OS. In the multivariate analysis, R-SYS-CNS, <3 cycles of HD-MTX, ECOG ≥2 and lack of consolidation remained significant. Lack of consolidation and receiving <3 cycles of HD-MTX were associated with inferior PFS in both univariate and multivariate analysis (figure 1). Conclusion Outcomes of aggressive B cell lymphoma with CNS involvement remain poor. The median OS was 8.3 months in our cohort. After adjusting for confounding factors, receiving >3 cycles of HD-MTX based regimen and consolidation with either WBRT or auto SCT were associated with improved outcomes. Pts with simultaneous CNS and systemic relapse had worse OS. Prospective studies are needed to evaluate optimal treatment for SCNSL.

Unraveling the Transcriptional Landscape of Nodular Lymphocyte-Predominant Hodgkin Lymphoma and T-Cell/Histiocyte Rich Large B-Cell Lymphoma: Impact of Tumor Microenvironment and Checkpoint Gene Expression

Introduction: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B-cell malignancy with a paucity of malignant cells embedded in a diverse tumor microenvironment (TME). The histological composition of the TME is known to influence outcomes, with nodular B-cell rich TME (classical histology, Fan patterns A&B) associated with indolent clinical course, while T-cell infiltration or diffuse growth (variant histology, Fan patterns C-F) may resemble aggressive T/cell-histiocyte rich large B-cell lymphoma (THRLBCL) to which NLPHL can transform. Molecular features of NLPHL and THRLBCL remain to be discovered. To gain further insights into the biology of these lymphomas, we recruited NLPHL and THRLBCL cases as part of the Atlas of Blood Cancer Genomes (ABCG) initiative, a consortium consisting of 26 institutions. Design: We collected comprehensive clinicopathological, treatment and outcome data from 154 NLPHL and 21 THRLBCL patients, with centralized pathology review performed by a panel of dedicated hematopathologists. Fan patterns of the NLPHL samples were documented in all samples where possible. RNA sequencing was performed on formalin-fixed paraffin-embedded (FFPE) diagnostic tumor samples (n=129 NLPHL; n=17 THRLBCL). Tumor-infiltrating immune cell compositions were enumerated using FARDEEP with signature matrix LM22 from CIBERSORT. Results: Median age at diagnosis for the patients with THRLBCL and NLPHL was 54 years (interquartile ratio [IQR] 43-65) and 40 years (IQR 24-53), respectively. The majority of patients with NLPHL had limited stage (74%), whereas the patients with THRLBCL predominantly had advanced stage at diagnosis (95%). In both diseases, most patients were males (NLPHL, 69%; THRLBCL, 76%). Spleen involvement was present in 11 NLPHL patients (8%) and histological growth pattern was documented in 112 patients (73%). Out of those, 47 (42%) presented with variant histology and 65 with classical histology. Variant histology was enriched in NLPHL patients with splenic involvement. During a median follow-up of 6.4 years (IQR 3.8-10.1), 12 NLPHL patients and 9 THRLBCL patients died. Patients with THRLBCL had worse 10-year overall survival (OS, 31% vs 89%; p<0.001) and progression-free survival (PFS, 30% vs 66%; p=0.002) compared to patients with NLPHL. Moreover, NLPHLs with variant histology had inferior 10-year OS compared to NLPHLs with classical histology (81% vs 91%; P=0.03; Figure 1). According to in silico immunophenotyping, THRLBCL cases had the highest median proportions of M1-macrophages (11.0%) and CD8+ T-cells (17.0%), followed by NLPHLs with variant histology (M1-macrophages, 6.5%; CD8+ T-cells, 14.5%), with the lowest proportion observed in NLPHLs with classical histology (M1-macrophages, 5.2%; CD8+ T-cells, 10.9%). In contrast, the median proportions of naïve B cells followed an opposite trend across subtypes (NLPHL classical histology, 15.5%; NLPHL variant histology, 11.0%; THRLBCL, 2.0%), whereas the median proportion of CD4+ T-cells was similar across both lymphomas (NLPHL classical histology, 33.9%; NLPHL variant histology, 33.9%; THRLBCL, 32.4%). Despite differences in the overall transcriptomic landscape, gene expression patterns posited THRLBCL and NLPHL as comprising a biological continuum. THRLBCL shared more similarities with NLPHL with variant histology, while NLPHLs with classical histology exhibited upregulation of genes related to cell growth and proliferation through the MYC pathway (P<0.001). Finally, we identified a strong association between THRLBCL and upregulation of checkpoint genes (P<0.001) and gene expression related to inflammatory response (P<0.001) (Figure 2). Furthermore, NLPHLs with a high checkpoint score (above the 75th percentile) were associated with spleen involvement (P<0.001) and worse outcome (5-year PFS 61% vs 87%; P=0.02). Conclusion: Our study provides the largest comprehensive clinical and transcriptomic analyses of NLPHL and THRLBCL to-date. The findings suggest that the inferior outcomes observed in THRLBCL and in a subset of NLPHL are attributable to a higher degree of inflammation in the TME, increased expression of checkpoint genes, and a high proportion of macrophages.

Ibrutinib, Fludarabine, Cyclophosphamide and Obinutuzumab (iFCG) for Firstline Treatment of Patients with CLL with Mutated IGHV and without Del(17p)/ TP53 Mutation: Six-Year Follow-up Analyses

Background Patients (pts) with IGHV-mutated ( IGHV-M) CLL have favorable long-term outcomes after receiving first-line FCR (fludarabine, cyclophosphamide and rituximab). We designed an investigator-initiated, phase II trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809), and we report here an updated analysis with a median follow-up of 72 months. Methods Inclusion criteria included diagnosis of previously untreated CLL/SLL needing treatment per iwCLL criteria, age ≥18, IGHV-M, absence of both del(17p) and TP53 mutation. Pts received 3 courses of iFCG. Pts achieving CR/CRi with undetectable MRD (U-MRD) in bone marrow (BM) (4-color flow-cytometry, sensitivity 10 -4) after 3 courses of iFCG received ibrutinib with obinutuzumab (iG) for 3 cycles, followed by ibrutinib monotherapy for 6 months. All other pts received iG for 9 cycles (C4-12). Pts with U-MRD (CR/CRi or PR) at end of Cycle 12 stopped all therapy, including ibrutinib. Response assessment was per 2008 iwCLL criteria with BM and CT scans every 3 months during the first year. After completion of all therapy, pts were followed by clinical examination, blood counts and peripheral blood MRD every 6 months. Results Between March 2016 and August 2018, 45 pts initiated treatment. Data cutoff was July 15, 2023. Baseline characteristics are shown in Table 1. All pts per study inclusion criterion had IGHV-M; however, 1 enrolled pt was later reclassified as IGHV-unmutated. A total of 69% pts had del(13q). After three cycles of iFCG, 39/45 (87%) pts achieved marrow U-MRD. Responses improved with continued therapy with 40/45 (89%) and 41/45 (91%) achieving marrow U-MRD after Cycles 6 and 12, respectively. Overall, 44/45 (98%) pts achieved marrow U-MRD as best response at any time during the study. Median follow-up duration is 72 months. 41/45 pts completed 12 cycles of treatment (4 pts came off study prior to Cycle 12). All 41 pts achieved marrow U-MRD and per protocol, discontinued ibrutinib. After a median follow-up of 61 mos post-discontinuing ibrutinib, 8 pts had MRD recurrence (defined as 2 consecutive values of ≥0.01% in peripheral blood by flow cytometry) at a median of 32 mos (range, 20-67 mos) after stopping all therapy. Of the 8 pts with MRD recurrence, 2 pts had clinical relapse (described below); remaining 6 pts are being monitored with no clinical progression or active therapy. The 6-year PFS and OS are 92.2% (95% CI= 77.7-97.4) and 97.7% (95% CI= 84.9-99.6), respectively. Two pts had clinical progression: one pt had IGHV 3-21; MRD recurred 28 mos after discontinuing ibrutinib, with clinical relapse 59 mos after discontinuing ibrutinib; this pt is now in remission with venetoclax-based therapy; the second pt with clinical relapse had IGHV-unmutated CLL, MRD recurred 24 mos after discontinuing ibrutinib, with clinical relapse 48 mos after discontinuing ibrutinib; this pt has not yet required therapy for relapse. No pt had progression to Richter transformation. One pt developed therapy-related myelodysplastic syndrome; this pt is being monitored for 58+ months without any active therapy for MDS with normal blood counts. One pt died from congestive heart failure during month 9 of the study. Conclusions iFCG regimen with only three cycles of combination chemotherapy achieves U-MRD rates of 98% in bone marrow on an intent-to-treat analysis and a 6-year PFS of 92% in IGHV-M CLL. These results are favorable compared to the 5-year PFS of approximately 65% with FCR (CLL10 trial) for the same genomic subgroup. Additionally, these results also appear favorable to the current targeted therapy regimens (such as BTKi, BCL2i+CD20 antibody) for IGHV-M CLL. With the caveat that the role of chemoimmunotherapy in CLL has significantly declined, the iFCG regimen provides for a very high rate of durable remissions among a chemo-sensitive subgroup of pts with CLL.

Risk and Response Adapted Approach for Treatment of Myeloma: Pushing Autologous Transplant Down the Hierarchy

Background & Significance: In current recommendations, consolidative autologous stem cell transplant (ASCT) is essential in management of NDMM. The IFM 2009 Trial showed that RVd followed by ASCT with 1-year lenalidomide maintenance was associated with a better PFS vs. RVd with 1-year lenalidomide maintenance alone (Attal M et al, NEJM 2017). A longer follow up (8 years) of IFM trial concluded that a delayed transplant (in 2 nd line) had no impact on the PFS2 (Perrot A et al, Blood 2020). We evaluated the merit of frontline ASCT (CR1) vs. post salvage ASCT (CR2) in light of indefinite maintenance therapy post novel triplet/quadruplet induction. Material & Methods: We conducted this retrospective analysis, of symptomatic myeloma patients who underwent ASCT at Rajiv Gandhi Cancer Centre, Delhi between April 2017 and October 2022. Patients were segregated into 2 cohorts; a) ASCT CR1- who received 4 to 6 cycles of RVd (+/- Anti CD38 antibody) induction followed by transplant and indefinite maintenance and b) ASCT CR2- patients who relapsed after 4-6 cycles of RVd induction+maintenance then salvaged with 2 to 6 cycles of novel agent-based therapy (Carfilzomib/ Pomalidomide/ Daratumumab) followed by ASCT and indefinite maintenance. Patient characteristics were balanced for age, gender, ISS, RISS and high risk cytogenetics (Del p53, t(4;14), t (14;16), 1qGain, 1pDel, 13qDel). Response was assessed as per IMWG criteria. PFS was defined as the time from induction/salvage to progression on next line of therapy or death. Results: Of 161 patients included, we compared outcomes of ASCT CR 1 (N=122) to ASCT CR-2 (N=39). All patients received maintenance (PI/IMID or in combination) post ASCT. Significant patients in ASCT-CR2 received novel salvage therapy (Carfilzomib/ Pomalidomide/ Daratumumab) (CR1-14 % vs CR2-100%, p value- <0.01). 86% patients in ASCT CR1 received RVd. Both groups were substantially exposed to Lenalidomide. Median time from diagnosis to transplant was 5.9 months (range 4-12) in ASCT- CR1 group and 29.5 months (range 18-64) in ASCT CR2 group (p value- 0.004). After a median follow up of 44 months for ASCT CR1 vs. ASCT CR2, the ORR (97% vs. 95.4%, p=0.88) and CR (85% vs. 78%, p=0.67), respectively. 42.6% patients in ASCT CR1 and 38.4% patients in ASCT CR2 relapsed (p value- 0.4%). The median PFS for both groups (ASCT CR1 and ASCT CR2) were similar 45 months and 43 months, respectively, (p value- 1.09). The 1-, 3- and 5-year PFS showed a similar trend across cohorts (CR-1: 95%, 59.1%, 39.7% and CR-2: 84%, 57.1%, 41.3%). Patients with high-risk cytogenetics in ASCT CR 1 (N=50) had a better median PFS (25 months) compared to ASCT CR2 (N=16, median PFS=17.9 months, p=0.059), fig:1 though statistically insignificant. Table:1 No difference in PFS for standard risk noted (p=0.38). On regression analysis, factors predictive of progression were: ISS stage III (univariate only), high-risk cytogenetics, IMID based maintenance therapy. We noted better PFS in patients receiving >24 months of maintenance. Depth of response prior to transplant, Melphalan dosage and remission (CR1 vs CR2) did not predict progression. Conclusion: In the light of above findings, does transplant decision need re-sequencing? Our findings are not in agreement with the hypothesis that exposure to novel agents in relapsed/refractory settings leads to resistant clone selection under stress. The pattern of relapse in standard risk myeloma remains same across lines of therapy. Excellent response rates are observed with novel agents at relapse therefore delaying transplant appears reasonable in standard risk. High-risk myeloma represents a unique subset where patients experience early/aggressive relapse indicating that current therapy offers little modification of kinetics or natural history of disease. Changing treatment paradigm based on disease risk and response appears pragmatic. Myeloma is the disease of elderly with plethora at hand, its time to individualize.

Helical Tomotherapy and Melphalan As the Conditioning Regimen in Autologous Stem Cell Transplantation for Multiple Myeloma with Extramedullary Plasmacytoma: A Single Center Clinical Research

Background Multiple myeloma(MM) is the second hematologic malignancy. Extramedullary myeloma indicates a poorer prognosis and survival. High dose Melphalan is the most widely used conditioning regimen. Helical tomotherapy(TOMO) is one of the most advanced intensity-modulated conformal radiotherapy technologies. We applied the combination of TOMO and Melphalan as the conditioning regimen in MM patients, and analyzed its efficacy and safety. Methods Clinical data were collected and compared between TOMO combined with melphalan group and non-TOMO group. SPSS V.25.0 was used for statistical analysis. Results Two methods were not significant difference by statistics analysis. The complete response rate of 100d in non-TOMO group significantly decreased compared to 1 month after transplantation (P=0.001). The 1-year PFS rate in the TOMO group was 86%, while non-TOMO group was 91%. There was no myeloma related death in the two groups within one year. TOMO group showed earlier enter platelet count below 20x109/L (P=0.003) and granulocyte deficiency (P=0.000). In terms of platelet implantation time,TOMO group was superior in platelet implantation time (P=0.041). No atrial fibrillation, heart failure, hepatic small vein occlusion, or transplant related death occurred during the transplantation period. Conclusion: The combination of TOMO and reduced dose Melphalan conditioning regimen is clinically feasible in terms of safety and efficacy evaluation. This scheme could improve the long-term survival of MM patients with extramedullary plasmacytoma.

Characteristics of Central Nervous System Relapse after CD19 CAR-T Cell Therapy in R/R NHL

Background CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable antitumor activity against relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). However, NHL with central nervous system (CNS) relapse carries a poor prognosis and high mortality. We reported an analysis of 80 patients with NHL who underwent CAR-T cell therapy, and described the characteristics including the international prognostic index (IPI) and other clinical variables to evaluate the outcomes of CNS relapse in NHL patients treated with CAR-T cell therapy. Methods A total of 80 patients with NHL treated with CD19 CAR-T cell therapy in our center between April 2017 and November 2022 was retrospectively analyzed. Patient characteristics, laboratory parameters, and clinical outcomes were collected. CNS relapse was diagnosed by cerebrospinal fluid cytology, MRI or PET-CT. Results Baseline characteristics of all 80 patients are summarized in Table 1. The median age was 58.5 (range, 10 to 79) years, and 57.5% of patients were male. Overall, 67 (83.8%) patients achieved complete remission (CR) or partial remission (PR) after CD19 CAR-T therapy. Seven (8.43%) patients developed isolated CNS relapse after CAR-T cell therapy, all of which were heavily pre-treated with multiple lines of chemotherapy prior to CAR-T cell therapy, and one of them had received autologous stem cell transplant before infusion of CAR-T cells. Only 4 of 7 patients with isolated CNS relapse achieved CR (n=4), and the median time to isolated CNS relapse from CAR-T cell infusion was 6.3(range, 1.53 to 25.8) months. Thirty-seven patients (46.2%) developed systemic recurrence without CNS involvement, with the median time from CAR-T to relapse of 3.2 (range, 0.467-30.8) months. The other 36 patients remained in remission at the last follow-up. During the median follow-up of 13.5 months of the whole cohort, the number of recorded deaths in isolated CNS relapse, systemic only recurrence, and no relapse patients was 5 (71.4%), 22 (59.4%), 1(2.78%), respectively. The 1-year OS and 1-year PFS of patients with isolated CNS recurrence was significantly lower compared to the no relapse group (OS, 35.7% [95%CI 12.1-100] vs 97.22% [95%CI 92-100], P<0.001; PFS, 28.6% [95%CI 8.86-92.2] vs 100% [95%CI 100-100], P<0.001), but showed no difference compared to the systemic only recurrence group(OS, 53.3% [95%CI 39.3-72.4], P=0.79; PFS, 13.0% [95%CI 5.53-30.5], P=0.17). Conclusion In conclusion, patients with CNS relapse showed significant difference in 1-year outcomes with no relapse group but not systemic relapse group in our study, which suggested the importance of effective prophylaxis against CNS relapse. Further investigation is necessary to better define the characteristics of patients who will benefit from prophylaxis. Acknowledgements We gratefully thank all the participation from patients enrolled in clinical trials (ChiCTR1800015575; NCT03118180; NCT04532281; NCT04532268; NCT04213469).

Oncologic outcomes of robot-assisted laparoscopy versus conventional laparoscopy for the treatment of apparent early-stage endometrioid adenocarcinoma of the uterus

ObjectiveTo compare long-term oncologic outcomes in patients with clinically uterine-confined endometrioid endometrial cancer who underwent surgical staging with robot-assisted (RA) versus conventional laparoscopy. MethodsWe performed a retrospective chart review of patients with newly diagnosed, uterine-confined endometrioid endometrial cancer who were treated and had primary surgery at our institution between 1/1/2009–1/1/2018. Clinicopathologic, surgical, and survival data were collected. Appropriate statistical methods were applied. ResultsOf 1728 patients identified, 1389 (80.4%) underwent RA and 339 (19.6%) conventional laparoscopy. At diagnosis, median age was 60 years (range, 24–92) and median BMI was 30.2 kg/m2 (range, 15.1–71.5). In the RA group, patients had longer operative time (170 vs 152 min, P < .001), lower conversion rate to laparotomy (0.6% vs 4.7%, P < .001), and a higher proportion had a BMI > 40 kg/m2 (17.2% vs 11.5%, P = .01) and same-day discharge (19.2% vs 5.3%, P < .001). Overall, 93% (RA) and 90% (conventional) of patients underwent lymph node assessment (P = .1). Comparing the RA versus conventional groups, final surgical stage on pathology (P = .6), median follow-up (55.7 vs 52.9 months, P = .4), and rates of perioperative complications (9.9% vs 7.7%, P = .6), recurrence (9.5% vs 7.4%, P = .3), 5-year PFS (88.5% vs 91.0%, P = .3), and 5-year OS (92.5% vs 92.4%, P = .7) were not significantly different. No significant increase in risk of recurrence (HR = 1.2, 95% CI: 0.8–1.9, P = .3) or poorer OS outcomes (HR = 0.9, 95% CI: 0.6–1.4, P = .7) were observed in the RA group. ConclusionIn uterine-confined endometrioid endometrial cancers, surgical staging using RA laparoscopy was not associated with adverse survival outcomes compared to conventional laparoscopy.

Analysis of baseline circulating tumor cells integrated with PET/CT findings in transplant-ineligible multiple myeloma

We aimed to improve prognostic predictors in transplant-ineligible multiple myeloma (TIE-MM) patients by combining baseline circulating clonal tumor cells (CTCs) and positron emission tomography/computed tomography (PET/CT) findings. The factors associated with prognosis were retrospectively investigated in 126 TIE-MM patients who underwent CTC quantification by multiparameter flow cytometry and PET/CT at the initial presentation. The total lesion glycolysis (TLG) level was calculated using Metavol software. The median percentage of CTC was 0.06% (range, 0%–4.82%), and 54 patients (42.9%) demonstrated high CTC levels. High CTC levels were associated with significantly poorer progression-free survival (PFS, 2-year 43.4% vs. 68.1%, P <0.001) and overall survival (OS, 5-year 39.0% vs. 68.3%, P <0.001). Similarly, high TLG levels significantly worsened the PFS (2-year, 41.2% vs. 67.6%, P = 0.038) and OS (5-year, 37.7% vs. 63.1%, P = 0.019). The multivariate analyses showed that Revised International Staging System (R-ISS) III, high CTC and TLG levels, and complete response were significant prognostic factors for PFS and OS. A novel predictive model was constructed using CTCs, TLG, and R-ISS III. The patients were stratified into three groups according to the number of risk factors, revealing an extremely high-risk group with a 2-year PFS of 0% and a 5-year OS of 20%. Patients without any high-risk features had better prognosis, with a 2-year PFS of 78.6% and a 5-year OS of 79.5%. The combination of CTCs and volumetric assessment of PET/CT at diagnosis augments the existing stratification systems and may pave the way for a risk-adapted treatment approach.

CTNI-20. NIMOTUZUMAB COMBINED WITH CONCURRENT CHEMORADIOTHERAPY IN THE TREATMENT OF NEWLY DIAGNOSED PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract BACKGROUND Newly diagnosed pediatric DIPG is a fetal disease with a poor prognosis and lacks of effective treatments. Multiple studies have demonstrated that the median survival time for patients is less than one year. A single-armed, prospective, multicenter study was conducted to evaluate the efficacy and safety of adding nimotuzumab to concurrent chemoradiotherapy for the treatment of newly diagnosed pediatric DIPG. METHODS Patients were 3-15 years old, histologically or imaging confirmed newly diagnosed DIPG, Lansky score ≥ 60, and at least one measurable lesion. Totally 48 patients were enrolled. Nimotuzumab (150mg/m2/w) concurrent chemoradiotherapy (Temozolomide: 75mg/m2 per day. Radiotherapy: 54Gy/30f) were administered for 6 weeks following a maintenance treatment (Nimotuzumab: 150mg/m2 biweekly. Temozolomide: 150-200mg/m2 per day for 5 days every 28 day). The primary endpoint was ORR, with secondary endpoints including 1-year OS rate, PFS and safety. RESULTS Between Apr 3, 2021 and Apr 13, 2023, a total of 48 patients were enrolled with a median age of 7 years old, in which 20 patients radiologically diagnosed DIPG, 28 patients histopathologically confirmed DIPG with 25 (89.3%) had H3K27M mutation. The median follow-up was 15.2 months. The ORR was 31.3% (95%CI, 18.66%-46.25%), mOS was 10.35 months, 1-year OS rate was 27.4% (95%CI, 14.73%-41.73%), mPFS was 6.93 months, and 1-year PFS was 9.5% (95%CI, 2.46%-22.56%). Eight patients (16.7%) experienced grade 3 or above ADRs. The most common toxicities were neutropenia (40%), leukopenia (25.0%), thrombocytopenia (25.0%). anemia (5.0%), flank pain (5.0%). CONCLUSIONS Nimotuzumab combined with concurrent chemoradiotherapy showed survival benifit for newly diagnosed pediatric DIPG patients with tolerable toxicity.

SURG-07. CLIVAL CHORDOMA: A COMPREHENSIVE META-ANALYSIS OF OPERATIVE MARGINS, PROGRESSION FREE SURVIVAL, AND OVERALL SURVIVAL

Abstract Despite their precarious behavioral classification (histopathologically benign (low-grade), behaviorally malignant), great strides have been taken to improve prognostication and treatment paradigms for patients with skull base chordoma. However, due to the rarity of this tumor, prior investigations remain limited to small retrospective series. Accordingly, we performed a systematic review and meta-analysis in order to profile surgical and survival outcomes for skull base chordoma. Fixed and random-effect meta-analyses were performed for categorial variables including number of males, GTR, STR, 5-year OS, 10-year OS, 5-year PFS, and 10-year PFS. Following the systematic search and screen, 47 studies published between 1993-2020 reporting data for 2204 patients remained eligible for analysis. Sex distribution was comparable between males and females, with a slight predominance of male-identifying patients (0.5625 [0.5418;0.3909]). Average age at diagnosis was 42.4 ± 12.5 years, while average age of treatment initiation was 43.0 ± 10.6 years. Overall, there was a substantial degree of heterogeneity across the 47 studies (I^2=56.3% [44.0%; 65.9%]). With respect to operative margins, the rate of GTR was 0.3323 [0.2824; 0.3909], I^2 = 91.9% [90.2%; 93.4%], while the rate of STR was significantly higher at 0.5167 [0.4596; 0.5808], I^2 = 93.1% [91.6%; 94.4%]. Interestingly, 5-year OS rate was 0.7113 [0.6685; 0.7568], I^2 = 91.9% [90.0%; 93.5%]. Furthermore, 10-year OS rate was 0.4957 [0.4230; 0.5809], I^2 = 92.3% [89.2%; 94.4%], which was comparable to both 5-year PFS rate of 0.5054 [0.4394; 0.5813], I^2 = 84.2% [77.6%; 88.8%] and 10-yr PFS rate of 0.4949 [0.4075; 0.6010], I^2 = 14.9% [0.0%; 87.0%]. There were 55 reported deaths for a perioperative mortality rate of 2.5%. The most common complication was CSF leak(5.4%). Overall, these results indicate good 5-year outcomes; however, 10-year prognosis for skull base chordoma remains poor due to its radiotherapeutic resistance and high recurrence rate.

CTNI-29. A PHASE 2 STUDY TO EVALUATE EFFICACY AND SAFETY OF ACT001 AND TEMOZOLOMIDE COMBINATION TREATMENT IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME

Abstract BACKGROUND Han Chinese patients with rGBM were randomly assigned to one of three cohorts in this phase 2 open label study: Arm A (ACT001, 400mg, BID), B (ACT001 and temozolomide combination) and C (TMZ or CCNU). Study endpoints include 1-year OS rate, PFS (by iRANO) and AE incidence. RESULTS 7, 6 and 6 patients were enrolled to Arms A, B and C respectively including one patient in Arm C with a mutant IDH1 (R132H). The median age was 52 years (range: 34-68) and male to female ratio 11/8. In addition to 7 SAEs, 189 TEAEs were reported in this interim analysis including 49 and 70 chemo-related AEs in Arm B and Arm C. Post enrollment MRI scans were performed in 6,6 and 4 patients in Arms A, B and C respectively. Despite the lack of objective response and difference in 1-year OS, a prolonged PFS lasting at least 12 months was noted in 3 patients including the patient with mutant IDH1 in Arm C (23 months and ongoing) and two patients in Cohort B (19 and 22 months, both ongoing) who were sensitive to TMZ in first line treatment as shown by at least 12-month interval between TMZ initiation and first relapse. Among 18 patients with wild type IDH, the prolonged stable disease was restricted to combination Arm whereas either the four patients with positive MGMT methylation or two patients with a similar history of sensitivity to first line TMZ treatment didn’t have such prolonged stable disease after being treated with TMZ or ACT001 alone during this study. CONCLUSIONS ACT001 restored sensitization of rGBM patients to TMZ treatment in sub-group of patients likely due to reduced DNA repair capacity by ACT001 treatment. Further study is warranted to evaluate the effect of ACT001 and TMZ combination in phase 2b study.