12-month Overall Survival Research Articles

Real-World Safety and Efficacy of Teclistamab for Patients with Heavily Pretreated Relapsed-Refractory Multiple Myeloma

Background: Teclistamab is a B-cell maturation antigen (BCMA) targeting bispecific T-cell engager approved in October of 2022 for patients with relapsed-refractory multiple myeloma (RRMM) who have received at least 4 prior lines of therapy (LOT) based on the results of the pivotal MajesTEC-1 trial. In this multicenter retrospective study, we evaluated the real-world safety and efficacy of teclistamab, highlighting patterns of utilization and outcomes, including patients who would have been considered ineligible for MajesTEC-1 trial. Methods: Five U.S. academic centers, part of the US Myeloma Innovations Research Collaborative (USMIRC), contributed data to this retrospective analysis, which included 102 patients with RRMM who received teclistamab as of 7/1/2023. Baseline characteristics were outlined by descriptive analysis. Teclistamab was administered in a step-up dosing manner as per the package insert. All patients had received at least the two step up doses and the first full dose of teclistamab. Patients received antimicrobial prophylaxis, supportive care, and toxicity management per institutional protocols. Responses to therapy including overall response rate (ORR), very good partial response (VGPR), and complete response or better (≥CR) were evaluated using the International Myeloma Working group (IMWG) criteria. Adverse events were graded based on the CTCAE v5.0 criteria. The Kaplan-Meier method was used for progression free survival (PFS), duration of response (DOR), and overall survival (OS) calculation. Results: Of the 102 patients included in this analysis, 25% were non-Hispanic Black and 44% had extramedullary disease (EMD); the median number of prior LOT was 6 (range 4-17). More than 80% (83/102) of the patients would not have met the MajesTEC-1 eligibility criteria; main reasons for ineligibility included: prior BCMA-directed therapy (BDT) (55%), ECOG performance status ≥2 (28%), and baseline cytopenias: grade 3-4 anemia (26%), and grade 3-4 thrombocytopenia (20%). All patients were triple class exposed and 92% were triple class refractory, 78% were penta-class exposed and 67% were penta-class refractory. More than half of the patients (55%) were refractory to prior BDT. Baseline characteristics are summarized in Table 1. Cytokine release syndrome (CRS) was observed in 65% of patients, all of which, except one, were grade 1-2 events, while immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 15% of the patients, with three patients having grade 3-4 events. The most common grade 3-4 hematological toxicities were neutropenia (23%), leukopenia (18%), thrombocytopenia (17%), and anemia (17%). Infections occurred in 28% of the patients, half of which were characterized as severe. The vast majority (80%) of infections involved the respiratory tract and 7% of patients discontinued teclistamab permanently due to recurrent or severe infections. After a median follow up of 3.2 months, the ORR was 64% for the entire cohort; ORR was 57%, 66% and 45% for patients who were BDT-refractory, penta-refractory, or had EMD, respectively. Of those who did respond, responses were found to be deep (72% ≥VGPR; 45% ≥CR). Patients that would have been ineligible for the MajesTEC-1 trial had an ORR of 59%. Detailed responses for the groups of interest are reported separately in Table 1. The estimated 6-month PFS, DOR, and OS of the entire cohort were 38% (95% CI, 26-56), 54% (95% CI, 34-85) and 68% (95% CI, 58-80), respectively (Figure 1). No treatment-related mortality was observed, although 26% of the patients had died at the time of data cut-off, with 89% of the deaths attributed to disease progression. Conclusion: This is the largest real-world experience of the safety and efficacy of teclistamab for RRMM. Overall, teclistamab was well tolerated with no major safety concerns, despite worse performance status and cytopenias than the MajestTEC-1 trial population. Moreover, despite the increased incidence of high-risk features, including penta-refractoriness, BDT refractoriness, and presence of EMD in this heavily pre-treated RRMM patient population, early efficacy assessment of teclistamab in a real-world setting was encouraging.

Clinical Outcomes of Patients with Relapsed/Refractory Follicular Lymphoma Treated with Tisagenlecleucel: Phase 2 Elara 3-Year Follow-up

Background: Tisagenlecleucel is approved in the United States and Europe for adults with relapsed/refractory follicular lymphoma (r/r FL) after ≥2 lines of prior therapy. The primary analysis of the Phase II ELARA trial (median follow-up: 17 months) reported high response rates and a favorable safety profile in heavily pretreated patients with r/r FL. Here we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after a median follow-up of more than 3 years. Methods: Eligible patients with r/r FL (grades 1-3A) previously treated with ≥2 lines of systemic therapy (including an anti-CD20 monoclonal antibody [mAb] and alkylating agent) received a single tisagenlecleucel infusion (0.6-6×10 8 CAR+ viable T cells). Bridging therapy was permitted. Baseline clinical characteristics and circulating blood naive T cells were correlated with clinical response. Cellular kinetics were assessed using quantitative polymerase chain reaction. Results: As of March 29, 2023, 97 patients were infused and had a median follow-up of 41 months (range, 34.2-49.7). At baseline, 68% of patients were double refractory to anti-CD20 mAb and alkylating agent, 65% had bulky disease (>7 cm or 3 lesions >3 cm), and 63% had progression of disease within 2 years of frontline systemic therapy (POD24). Comorbidities included cardiac disorders (9%), diabetes (9%), and renal insufficiency (5%). Among 94 patients evaluable for efficacy, best overall response (BOR) of complete response (CR) rate by independent review committee assessment was 68% (95% CI, 57.7%-77.3%) and overall response rate (CR + partial response) 86% (95% CI, 77.5%-92.4%). Median progression-free survival (PFS) was 37 months; 36-month PFS was 53% in all patients and 69% in patients with a BOR of CR. In the POD24 subgroup, 36-month PFS was 50% (n=61) compared with 59% for patients without POD24 (n=33) (Figure). CAR transgene persistence was observed for up to 1290 days. Patients without POD24 had higher median in vivo CAR expansion and longer persistence than patients with POD24. Median duration of response (DOR) was not reached; 64% of responding patients had ongoing response at the time of the 36-month analysis. Among patients with a BOR of CR, 73% had an ongoing response at the time of the 36-month analysis. High baseline levels of circulating CD8+ naive T cells (>2.14% of total T cells) were associated with prolonged PFS and DOR. Median overall survival (OS) and median time to next treatment were not reached. The OS rate at 36 months was 82%, and probability of starting a new treatment at 36 months was 35%. In the POD24 subgroup, 36-month OS rate was 83% compared with 81% in patients without POD24 (Figure). No new safety signals were reported. The most common grade ≥3 adverse events (AEs) were neutropenia (43%) and anemia (19%). The most common serious AEs were cytokine release syndrome (20% [Lee grading]), pneumonia (11%), and febrile neutropenia (8%). To date 18 patients have died during the study (progressive disease, n=8; AE, n=9; euthanasia, n=1). Conclusions: Patients with r/r FL maintained a high rate of durable responses more than 3 years after tisagenlecleucel infusion, including patients in high-risk subgroups such as POD24. Tisagenlecleucel's safety profile remains favorable with no new safety signals during extended follow-up. Correlative analyses suggest higher baseline levels of CD8+ naive T cells (>2.14%) are associated with improved long-term clinical outcomes.

Real-Life Experience of the Combination of Daratumumab, Bortezomib, Melphalan, and Prednisone (DVMP) in Patients with Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem-Cell Transplantation

INTRODUCTION The combination of daratumumab, bortezomib, melphalan, and prednisone (D-VMP) is an effective and safe alternative treatment for patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous hematopoietic stem-cell transplantation (HSCT) as described in ALCYONE clinical trial. However, real-life data is limited. This study aims to evaluate the data derived from real-life experience with this combination. METHODS This is a Spanish retrospective, multicenter study. One hundred eleven adults with NDMM ineligible for autologous HSCT who had started first-line treatment with D-VMP from 01/Jun/2019 to 01/Apr/2023 were included. The primary endpoint was to describe the progression-free survival (PFS), and the secondary endpoints were to describe overall response rate (ORR), very good partial response (VGPR), complete response (CR), overall survival (OS), and safety profile. RESULTS A total of 111 patients were included, 57 (51%) were males. The median age was 77 years (IQR 73-82), with 67% ≥ 75 years. Seven percent had an ECOG >2, 6% severe anemia (Hb <7.5g/dL), 14% creatinine >2mg/dL, and 7% had a first in-hospital dialysis. Twenty-one (19%) had R-ISS III disease stage, and 22 (20%) had extramedullary disease (16% bone-related plasmacytomas and 4% soft-tissue plasmacytomas). Of the 95 patients evaluable for cytogenetics, 13 (14%) had t(11;14), 36 (38%) had at least one poor-prognosis cytogenetic abnormality (del17p, t(4;14), t(14;16), gan/amp(1q) or del(1p)), and 10 (10%) had > 1. Of all patients, 83 (75%) had completed induction, with a median number of cycles of 9 (IQR 6-9). Among these patients, 26 (23%) received combined maintenance with daratumumab and bortezomib. The ORR was 91%, with at least VGPR in 66% of patients. The ORR and VGPR/CR rates were consistent regardless of age (ORR >74 years 86% vs <75 years 92%; VGPR/CR >74 years 67% vs <75 years 62%) and cytogenetic risk (ORR high-risk cytogenetic 86% vs standard cytogenetic 94%; VGPR/CR high risk cytogenetic 64% vs standard cytogenetic 68%). The median time to response was 35 days (IQR 24-49), and the median time to best response was 206 days (IQR 91-458). Minimal residual disease (MRD) was determined in 27 (54%) of patients in CR and 6 (26%) in VGPR. Eighteen patients in CR and 1 patient in VGPR had negative MRD (at least 10 -4). Twelve patients with negative MRD were subsequently re-evaluated, and 7 maintained MRD negativity at 4 (1), 6 (2), 9 (2), 12 (1) and 24 (1) months. Median OS was 44 months (95% confidence interval [CI], 33 to 55) and median PFS was 28 months (95% CI, 21 to 36). At a median follow-up of 22,6 months (IQR 15-30), the 36-month OS rate was 60% (95% CI, 52 to 68). Median OS was 36 months (95% CI 24 to 45) in the high cytogenetic risk group. Median PFS was 22 months(IC 95% 7 to 38) in the high cytogenetic risk group and 9 months (IC 95% 0 to 22) in the group with > 1 poor-prognosis cytogenetic abnormality. The dose of bortezomib was reduced in 42% of patients, mainly due to neuropathy (42%). The dose of melphalan was reduced in 28%, mainly because of myelotoxicity (29%) and kidney failure (19%). Both bortezomib and melphalan were discontinued in 6% of patients. Daratumumab did not require adjustment or early suspension. There were 13 deaths (12%), 4 due to progression, 4 due to infection, and 5 due to a cause unrelated to the MM. Among 24 (22%) of total patients who experienced relapse, 96% received subsequent therapy. The most frequent therapy was Lenalidomide-Dexamethasone (46%) followed by Carfilzomib-Lenalidomide-Dexamethasone (38%). CONCLUSIONS In real-life practice, D-VMP combination in patients with NDMM ineligible for transplant showed comparable efficacy and safety profile with those reported in ALCYONE clinical trial. Although the PFS and OS data are lower than those reported in ALCYONE, this could be due to the older age and a worse clinical involvement of the patients included in this study.

Efficacy and Safety of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Treatment-Naive, Higher-Risk Myelodysplastic Syndromes

Introduction: Azacitidine (Aza) has been shown to prolong survival in patients with treatment-naive, higher-risk myelodysplastic syndrome (HR MDS) compared to lower-intensity, conventional treatment regimens; however, improvement in clinical outcomes are needed. Clinical data on the synergy of Aza with venetoclax (Ven)-a selective, potent BCL-2 inhibitor-in the treatment of myeloid malignancies and the unmet need in HR MDS provide a rationale to evaluate Ven in combination with Aza in treatment-naive HR MDS. Here, we report efficacy and safety data in patients with treatment-naive HR MDS treated with Ven+Aza at the recommended Phase 2 dose (RP2D) in the safety expansion part of the Phase 1b study (NCT02942290). Methods: Adult patients were enrolled with de novo treatment-naive HR MDS defined by the Revised International Prognostic Scoring System (IPSS-R) score of >3 with an Eastern Cooperative Oncology Group performance status of ≤2, and bone marrow (BM) blasts <20% at baseline. Patients received Ven 400 mg orally daily on Days 1-14 and Aza 75 mg/m 2 intravenously or subcutaneously on Days 1-7 or on Days 1-5, 8, and 9 of each 28-day cycle (RP2D). The primary objective was to assess the complete remission (CR) rate. Key secondary objectives included determining marrow CR (mCR), overall response rate (ORR), hematologic improvement (HI), postbaseline red blood cell (RBC) and platelet transfusion independence (TI), overall survival (OS), duration of CR, time to next treatment (TTNT), transformation to acute myeloid leukemia (AML), and time to AML transformation. Responses were assessed by International Working Group 2006 criteria. Prophylactic antibiotics were mandated in Cycle 1 and recommended for Grade ≥3 neutropenia thereafter. Safety was analyzed in patients who received ≥1 dose of study treatment. Results: At thedata cutoff of May 31, 2023, 107 patients had received Ven+Aza at the RP2D. Key baseline characteristics for all treated patients are shown in Table 1A. Median age was 68 years (range, 26-87), 64% of patients had intermediate or poor cytogenetic risk, and >89% had ≥5% BM blasts. Median number of treatment cycles before transplantation was 3.0 (range, 1.0-11.0). At the median follow-up of 31.9 months (95% CI, 30.4-42.5), CR rate was 29.9% (95% CI, 21.4-39.5), with a median CR duration of 16.6 months (95% CI, 10.0-not reached [NR], Table 1B). Median OS was 26 months (95% CI, 18.1-51.5), with an estimated 12-month OS of 71.2% (95% CI, 61.4-78.9)and 24-month OS of 51.3% (95% CI, 41.2-60.5). Median OS for CR was NR. Median TTNT including transplantation was 6.8 months (95% CI, 5.6-8.3). Sixty-two (57.9%) patients received subsequent treatment, including transplantation in 42 (39.3%) patients; the median time to transplantation was 4.8 months (range, 1.4-16.8). Among patients who received transplantation post-study, 17 were transplant ineligible at study entry. Postbaseline TI rate was 61.7% for RBC and 72.0% for platelets. Median maximal duration of TI achieved was 5.4 months (range, 1.8-50.8) and 5.4 months (range, 1.9-56.0) for RBC and platelets, respectively. Postbaseline overall hematologic improvement (HI) was achieved in 51 (49.0%) of 104 evaluable patients, and specific responses included erythroid (40/93; 43.0%), platelet (32/74; 43.2%) and neutrophil (10/57; 17.5%) indices. All patients experienced ≥1 treatment-emergent adverse event (TEAE), with 94.4% of patients reporting grade ≥3 TEAEs. Serious adverse events (SAEs) occurred in 68.2% of patients. Common TEAEs of any grade were constipation (53.3%), nausea (49.5%), neutropenia (48.6%), thrombocytopenia (44.9%), febrile neutropenia (42.1%), diarrhea (41.1%), anemia (39.3%), vomiting (36.4%), and hypokalemia (26.2%). Grade ≥3 TEAEs reported in ≥20% of patients were neutropenia (48.6%), thrombocytopenia (43.0%), febrile neutropenia (42.1%), and anemia (34.6%). Infections were reported in 57% of patients, including SAEs in 40.2% of patients. Of the 59 deaths (55.1%) reported, 23 (21.5%) were due to disease progression and 7 (6.5%) to adverse events. Within 60 days after study start, 7 deaths (6.5%) were reported. Conclusion: Ven 400 mg for 14 days plus Aza combination was well tolerated with favorable responses of CR+PR+mCR in >80% and HI in nearly 50% of patients with treatment-naïve HR MDS. A separate Phase 3 study of this combination is ongoing to confirm survival benefit.

Real-World Tisagenlecleucel Outcomes in Richter-Transformed Chronic Lymphocytic Leukemia: A Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis

Background: Richter transformation (RT) is a rare but serious transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly large B-cell lymphoma (LBCL). There is currently no standard therapy for RT lymphoma and median overall survival (OS) is estimated to be only 8-12 months. Tisagenlecleucel is an autologous CD19-directed chimeric antigen receptor (CAR)-T cell therapy approved for the treatment of r/r LBCL in patients who have received ≥2 lines of prior therapy. Here, we describe the efficacy and safety of tisagenlecleucel in patients with RT in a real-world setting with a median follow-up (infusion to data cutoff) of 31 months. Methods: Data were collected as part of a noninterventional, prospective, longitudinal study using the CIBMTR registry. All patients were treated in the United States, Canada, or Israel. Efficacy outcomes analyzed included overall response rate (ORR), progression-free survival (PFS), and OS. Safety outcomes included the incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: As of May 4, 2023, 48 patients with RT received a single tisagenlecleucel infusion. The median age at infusion was 68 years (range, 39-83). Fifty-eight percent of patients were ≥65 years old. The median number of all prior lines of therapy was 3 (range, 1-8); 42% of patients received ibrutinib as a prior therapy. No information confirming clonal relation of LBCL to CLL in evaluated patients was available. Fifty percent of patients had primary refractory disease. Prior to infusion, 46% of patients were reported to have elevated lactate dehydrogenase (LDH). Two patients who received tisagenlecleucel infusion, and were alive at data cutoff, had not yet reached 100 days post-infusion and were therefore not evaluable for efficacy and safety. Among the 46 patients evaluated for efficacy and safety, the ORR (complete response [CR] + partial response) was 63% (95% CI, 47.5-76.8) and CR rate was 50% (n=23). In total, 23 patients (23/46, 50%) experienced disease relapse, 17 within 6 months of infusion (Figure). Twelve- and 24-month PFS were 43% and 39%, respectively; 12- and 24-month OS rates were 51% and 44%, respectively. Among 23 patients with a best overall response of CR, 57% remained in remission at data cutoff. The most common adverse events of any grade were CRS (78%), hypogammaglobinemia (46%), and ICANS (35%). Grade 3/4 CRS was reported in 11% of patients. No patient experienced grade 5 CRS. CRS was managed with tocilizumab in 81% of cases. Grade 3 ICANS was reported in 9% of patients. No grade 4/5 ICANS events were observed. Two patients went on to receive a stem cell transplant following tisagenlecleucel infusion. In total, 25 deaths were reported. The most common cause of death was progressive disease (13/48, 27%). Twelve patients (12/48, 25%) died in the absence of disease progression. Causes of non-relapse-related mortality included infection (including COVID-19, n=5), respiratory failure (n=2), malignant neoplasm (n=2), prior malignancy (n=1), multiorgan dysfunction (n=1), and severe veno-occlusive disease (n=1). Conclusions: In the largest cohort of patients with RT receiving treatment in a real-world setting, tisagenlecleucel resulted in a high overall response rate and durable survival. The incidences of CRS and ICANS were similar to other real-world reports of tisagenlecleucel for patients with LBCL. Overall, these findings demonstrate that tisagenlecleucel could be considered a potential treatment option for patients with RT who have a high unmet medical need.

Favezelimab in Combination with Pembrolizumab in Patients with Anti-PD-1-Naive Relapsed or Refractory Classical Hodgkin Lymphoma: Updated Analysis of an Open-Label Phase 1/2 Study

Introduction: Programmed cell death protein 1 (PD-1) inhibitors such as pembrolizumab play an important role in the treatment of patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but treatment failure remains a significant challenge. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor that downregulates T-cell activity and plays a role in regulating T-cell function. Dual blockade of PD-1 and LAG-3 demonstrated antitumor activity in patients with advanced melanoma in the RELATIVITY-047 trial, which led to FDA approval in this setting. Favezelimab is a humanized IgG4 monoclonal antibody directed against LAG-3 that is being investigated in combination with pembrolizumab in patients with R/R hematologic malignancies in a multicohort phase 1/2 study (NCT03598608). Prior analyses of this study demonstrated that pembrolizumab 200 mg plus favezelimab 800 mg every 3 weeks (Q3W) exhibited sustained antitumor activity and acceptable safety in the cohort of patients with anti-PD-1-naive R/R cHL (cohort 1). We present updated results from this cohort. Methods: A safety lead-in phase to determine the recommended phase 2 dose (RP2D) was followed by a dose-expansion phase. Eligible patients were ≥18 years of age; had R/R cHL after autologous stem cell transplantation (ASCT), were ineligible for ASCT, or did not respond to salvage chemotherapy; had not received prior anti-PD-1 therapy; and had an ECOG performance status of 0 or 1. In the safety lead-in, patients received pembrolizumab 200 mg IV Q3W and favezelimab at a starting dose of 200 mg that was escalated to 800 mg IV Q3W using a modified toxicity probability interval method. In the dose-expansion phase, patients received pembrolizumab 200 mg Q3W plus favezelimab at the established RP2D of 800 mg Q3W for up to 35 cycles (~2 years). CT was performed every 12 weeks and PET at weeks 12 and 24. The primary end point was safety. Objective response rate (ORR) per IWG 2007 criteria by investigator review was a secondary end point. Duration of response (DOR) and progression-free survival (PFS) per IWG 2007 criteria by investigator review and overall survival (OS) were exploratory. Results: Thirty patients with anti-PD-1-naive cHL were enrolled in cohort 1. The median age was 40.5 years (range, 19-82), 17 patients (57%) were male, 16 (53%) had an ECOG performance status of 0, and 24 (80%) had received 3 or fewer prior lines of therapy. At data cutoff (March 2, 2023), 13 patients (43%) had completed 35 cycles of study treatment, 16 (53%) had discontinued treatment (10 [33%] progressive disease, 5 [17%] adverse event [AE], 1 [3%] noncompliance with study drug), and 1 (3%) was ongoing on treatment. The median time from first dose to data cutoff was 31.5 months (range, 24.0-43.2). Treatment-related AEs occurred in 27 patients (90%), of which the most common (≥20%) were hypothyroidism (27%), infusion-related reaction (23%), and fatigue (20%). Grade 3/4 treatment related AEs occurred in 9 patients (30%). Five patients (17%) discontinued treatment because of treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 20 patients (67%); 3 patients (10%) had grade 3 events (colitis, pneumonitis, severe skin reaction) and 1 patient (3%) had a grade 4 event (hepatitis). Of 5 patients who received allogeneic stem cell transplantation after discontinuation or completion of study treatment, 1 had a grade 3/4 AE (increased blood bilirubin) that was unrelated to study treatment and resolved. The ORR was 80% (n = 24; 95% CI, 61-92); 10 patients (33%) had a complete response and 14 (47%) had a partial response. Twenty-nine patients (97%) had any reduction in target lesions size from baseline, and 25 (83%) had a reduction of ≥50%. Median DOR was 17.0 months (range, 2.6-30.2), and an estimated 47% of responders remained in response ≥24 months. Median PFS was 19.4 months (95% CI, 9.0-28.5), and the 24-month PFS rate was 46%. Median OS was not reached (NR; 95% CI, NR-NR), and the 24-month OS rate was 93%. Conclusion: With additional follow-up, the combination of favezelimab and pembrolizumab continued to demonstrate sustained antitumor activity and manageable safety in patients with anti-PD-1-naive R/R cHL. Analyses are underway to identify biomarkers predictive of response to the combination of favezelimab and pembrolizumab. Further studies to investigate this combination are warranted.

Venetoclax Combined with Homoharringtonine and Cytarabine ( HAV) As Induction Treatment in Elder or Intensive Chemotherapy (IC) Ineligible Patients with Newly Diagnosed Acute Myeloid Leukemia

INTRODUCTION In recent years, venetolax (Ven)-based combination therapy has significantly improved the efficacy of patients with newly diagnosed acute myeloid leukemia (AML). In CAVEAT trial (VEN+IA), both 200mg and 400mg Ven combining with IA 2+5 achieved promising results. Homoharringtonine (HHT, omacetaxine mepesuccinate) is an alkaloid derived from trees of the genus Cephalotaxus. HHT combined with Ara-C (HA) based regimens as induction regimen have been used broadly in new diagnosed AML patients in China. Previous reports shown that HHT could inhibit the anti-apoptotic protein MCL-1, BCL-XL and may exert a synergistic effect when combining with Ven. Therefore, we designed the VEN combining HA (HAV) as induction regimen in newly diagnosed AML patients. We retrospectively collected and analyzed the clinical data of HAV as induction treatment in thirty-threeelder or intensive chemotherapy ineligible patients with newly diagnosed AML. The purpose of this study was to evaluate the efficacy and safety of the regimen. METHODS Retrospectively collected and analyzed the clinical data of thirty-three patients treated with Ven+HA as induction therapy between July 2020 and April 2023. The induction regimen consisted of oral Ven (100mg Day 0; 200mg Day 1-14), intravenous HHT (2 mg/m², days 3-9), and cytarabine (50 mg/m 2, days 3-9). After achieving CR or CRi, allogeneic hematopoietic stem-cell transplantation (Allo-HSCT) were recommended according to ELN guideline and Chinese guidelines for the diagnosis and treatment of adult AML. Patients who are ineligible to allo-HSCT received consolidation and maintenance therapy. The consolidation therapy included two cycles of Ven combining with intermediate-dose Ara-C (Ven 400 mg on Days 1-7, Ara-C 1 g/m 2/q12 h Days 2-4, or Ara-C 0.5g/m 2/q12h Days in the patient older than 65 years ), one cycles DA (DNR 45 mg/m², Days 1-2 and Ara-C 100 mg/m², Days 1-5) chemotherapy and two cycle HA (HHT 2 mg/m², Days 1-5 and Ara-C 100 mg/m², Days 1-5). Patient (intermediate and adverse risk) who remained in CR after consolidation therapy received maintenance therapy. The maintenance treatment adopted AZA (100 mg/d, Days 1-5) every month for at least four cycles. The primary purpose was evaluated the efficacy and safety of HAV regimen in elder or intensive chemotherapy ineligible patients with de novo AML. Secondary purpose was overall survival (OS), event-free survival (EFS), disease-free survival (DFS). RESULTS Until April 2023, thirty-three patients with de novo AML were treated with HAV as induction therapy. Baseline characteristics of the 33 patients are shown in table 1. The ORR (CR+PR) after one cycle of induction was 90.9% (95% CI, 80.6-100%)with CR rate of 87.9% (95% CI, 76.1-99.6%). Moreover, 79.3% (23/29) of the CR patients were MRD undetectable (95% CI 63.6-95.0%). Grade 3 or worse adverse effects included neutropenia (100%), thrombocytopenia (100%), febrile neutropenia (100%). None of patients died during the induction therapy. The median neutrophil and platelet recovery times were 10 (range: 5-15) and 10 (range: 3-17) days, respectively. Until June 30, 2023, with a median follow-up of 10 (2-23) months, 5 patients proceed allo-HSCT, the estimated 12-month OS, EFS, and DFS rates were 83.0% (95% CI: 73.4-92.6%), 71.3% (95% CI: 60.0-82.6%), and 75.9% (95% CI: 64.4-87.4%), respectively. (Figure 1) Conclusion: HAV is a highly effective and safe induction therapy for elderly or IC ineligible newly diagnosed AML. 【Keywords】Venetoclax; HAV; AML; induction treatment; elder ; ineligible

Outcomes of Venetoclax-Based Therapy in Patients with Daratumumab-Refractory t(11;14) Positive Light Chain Amyloidosis

Background: Light chain (AL) amyloidosis is a rare plasma cell disorder (PCD) characterized by misfolded light chains produced by clonal plasma cells leading to organ dysfunction. Over the past few years, the introduction of daratumumab (dara), a CD38 monoclonal antibody, into clinical practice has markedly improved outcomes, however, relapses still occur with limited available options. Venetoclax (VEN) is a BCL-2 inhibitor that has shown encouraging clinical efficacy in PCDs harboring the translocation between the chromosomes 11 and 14 (t[11;14]). The aim of this study was to evaluate the efficacy of VEN-based therapy (VBT) in patients with dara-refractory AL who were positive for t(11;14). Methods:Of all adult patients with systemic AL amyloidosis evaluated at our center between 1/2016 and 7/2023, we focused on those who had prior refractoriness to dara (dara was given at any time during the disease course, as frontline or salvage treatment) and received VBT (at any time after dara refractoriness). Data was obtained via retrospective chart review. Hematologic responses including complete response (CR), very good partial response (VGPR) and partial response (PR) were according to the AL consensus criteria. No patients had concomitant multiple myeloma. Baseline characteristics were outlined by descriptive analysis. Kaplan-Meier method was used for progression free survival (PFS), time-to-next-treatment (TTNT) and overall survival (OS) calculations. Results: A total of 21 patients who met the above criteria, were included in this analysis. The median age of patients was 65 (range 48-80) years, median number of prior lines of therapy (LOT) was 2 (range 1-5) and median percentage of bone marrow plasma cells prior to VBT initiation was 15 (range 5-40). Fifteen (71%) patients had cardiac involvement, 11 (52%) renal involvement, and 7 (33%) in addition to other organs had bone marrow involvement; 67% of patients had >2 organs involved. Of the entire cohort, 24% had undergone autologous hematopoietic cell transplant (AHCT) as frontline therapy. All patients had t(11;14) and one patient had an additional 1q gain. The baseline characteristics are summarized in Table 1. VEN was given in combination with: dexamethasone (VEN-dex) in 9 patients (43%), daratumumab-dex (VEN-dara-dex) in 6 patients (28.5%) and proteasome inhibitor-dex (VEN-PI-dex) in 6 patients (28.5%). The median duration on VBT was 9 (range 1.5-24.1) months. At data cut-off, 5 patients had discontinued therapy because of ongoing CR/VGPR, 1 due to ongoing fatigue and 6 due to disease progression or death. The hematologic overall response rate (ORR) was 95% with 11 (53%) patients achieving CR or better and 7 achieving (33%) VGPR. Patients responded rapidly, with a median time to best hematologic response being 2 (range1-5) months. Among the 18 (86%) patients who achieved >VGPR, 15 also achieved difference of free light chains (dFLC) <10 mg/l. Of the 15 patients with cardiac involvement, 6 (40%) achieved response to VBT, while 4 (27%) were non-evaluable (3 had maintained response from previous LOT and 1 had undergone heart transplant); the remaining 5 (33%) had stable disease without response. Of the 11 patients with renal involvement, 4 (36%) achieved organ response to VBT, while 2 (18%) were non-evaluable (1 had maintained response from previous LOT and 1 had undergone kidney transplant); the remaining 5 (46%) had stable disease without response. Eventually, 4/21 patients experienced disease progression. The median PFS for the entire cohort was not-reached (NR); the 6 and 12-month PFS rates were 83% and 68% respectively. Median TTNT was also NR. At data cut-off, 3 patients had died (2 from cardiac complications [cardiac arrest and heart failure], and 1 from dialysis complications). The median OS was NR; the 6- and 12-month OS rates were 89% and 83%, respectively. Conclusion: Our findings suggest that VEN is effective in t(11;14) positive relapsed-refractory AL amyloidosis in combination with dexamethasone alone or with other established plasma-cell directed agents. VBT led to deep and rapid overall response rates with more than 80% of patients achieving VGPR after exposure to only 2 cycles of therapy. This is critical in the setting of dara-refractoriness where therapeutic options are very limited. A clinical trial is ongoing to further evaluate the role of VEN in relapsed-refractory AL amyloidosis.

Tislelizumab Plus Zanubrutinib in Patients with Richter Transformation: Primary Endpoint Analysis of the Prospective, Multi-Center, Phase-II RT1 Trial of the German CLL Study Group

Background Richter transformation (RT) describes the development of an aggressive lymphoma, in most cases a diffuse large B cell lymphoma (DLBCL) or Hodgkin's lymphoma (HL), in patients (pts) with chronic lymphocytic leukemia (CLL). Pts with RT have a dismal prognosis with chemoimmunotherapy (CIT) like R-CHOP, with overall response rates (ORR) of <40% and median overall survival (OS) of 6-8 months. Targeted therapies have the potential to improve outcomes, but few prospective studies have been run in this entity. Here we present the first data of the international phase-II RT1 trial, in which the PD1 inhibitor tislelizumab is combined with the next-generation BTK inhibitor zanubrutinib to treat pts with RT. Methods Pts with histologically confirmed RT (DLBCL or HL [HL only when not eligible for standard therapy]) and up to one prior line of RT-directed therapy were eligible. Each cycle (of 21 days) consisted of one infusion of 200 mg tislelizumab at day 1 and 160 mg zanubrutinib twice daily orally. Six cycles of induction were followed by 6 cycles of consolidation; pts with complete response (CR), partial response (PR) or stable disease (SD) continued maintenance until disease progression/non-tolerance. The primary endpoint was ORR after induction therapy for pts receiving ≥ 3 cycles according to the refined Lugano Classification with the aim to test the null hypothesis of ≤0.40. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), OS and time to next treatment (TTNT). Results Of 59 enrolled pts, 48 pts received at least 3 cycles of treatment and comprised the analysis population according to the study protocol. Eleven pts stopped earlier due to withdrawal, death, PD or toxicity. Median observation time was 13.9 months (interquartile range 1.7-35.9). Median age was 67 years (range 45 - 82). 22 (45.8%) pts had ECOG 1 or higher. Median LDH at enrollment was 335 U/l. Sixteen (34.8%) pts had del(17p)/ TP53mut, 29 (70.7%) pts had unmutated IGHV. 25 (64.1%) pts had high or very high-risk CLL according to CLL-IPI, 11 (28.2%) intermediate and 3 (7.7%) low risk. Complex karyotype (≥3 aberrations) was detected in 16 (42.1%) pts. 46 (95.8%) pts had DLBCL-RT and 2 (4.2%) pts had HL-RT. In 26 (54.2%) pts, the RT was reported as clonally related to the CLL (22 [45.8%] unknown). Overall, 36 (75.0%) pts had received prior CLL-directed therapy, including CIT (25 pts) and targeted agents (32 pts) as well as prior allogeneic stem cell transplant (SCT) in 3 pts. 12 (25.0%) pts had treatment-naive CLL. Thirteen pts (27.1%) had received prior RT-directed therapy, including CHOP-like regimens and BTK inhibitors. 35 (72.8%) pts had not received prior RT-directed therapy. Twenty-eight of 48 pts responded to induction therapy resulting in an ORR of 58.3% (95% CI, 0.43-0.72), including 9 (18.8%) CR and 19 (39.6%) PR, meeting the study's primary endpoint (p=0.008) (Fig A). SD was reported in 6 (12.5%) pts, 11 (22.9%) pts had progressive disease (PD), three had missing assessment due to PD. The median DOR was not reached, the 6-month DOR rate was 70.6%. Median PFS was 10 months (95% CI 3.8 -16.3) with a 12-month rate of 46.9% (Fig B). Median OS was not reached (12-month OS rate 74.7%). Median TTNT was not reached (12-month TTNT rate 56.2%). Post-protocol treatment included CIT in 21 cases (48.8%), radiation in 1 case (2.3%), BTK/BCL2 inhibition in 7 (16.3%) cases and 8 (18.6%) allogeneic SCT. SCT was conducted as consolidation in two pts with PR, and as salvage treatment for 5 pts with SD/PD (one missing response). Overall, 606 adverse events (AEs) were reported, of which 173 (28.5%) were ≥ grade 3 and 129 (21.3%) were serious AE. Of the 29 pts who discontinued study treatment, three were due to toxicity, the rest for PD and/or start of next line of therapy. The most frequent AEs were infections and infestations (17.7%), including Covid-19, pneumonia and urinary tract infections, gastrointestinal disorders (12.7%), including diarrhea and nausea, and blood and lymphatic system disorders (11.2%), including anemia, neutropenia and thrombocytopenia. Conclusions Combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for pts with RT. Responses are durable and overall survival in the RT1 study is encouraging given the otherwise poor prognosis of RT. Translational studies are ongoing to identify predictors of response to checkpoint inhibition in RT.

Centralized MRD Assessment at Early Timepoints in Gimema AML1718 Trial, a Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk AML

Background: New therapeutic strategies are strongly needed to improve the prognosis of high risk Acute Myeloid Leukemia (AML) patients, such as combination of novel agents and conventional chemotherapy. The Italian GIMEMA AML1718 trial (NCT03455504) investigate the safety and efficacy of the BCL-2 inhibitor venetoclax (VEN) in combination with intensive fludarabine-based induction (FLAI) [fludarabine 30 mg/sqm from day 1 to day 5, cytarabine 2000 mg/sqm from day 1 to day 5, and idarubicin 8 mg/sqm on days 1, 3 and 5] as first-line therapy for newly diagnosed non low-risk ELN AML patients. Results from the Planned Interim Analysis of Safety Run-in and Part 1 (early expansion cohorts) were presented at the last 2022 ASH Meeting. Median overall survival (OS) was not reached; probability of 12-month OS was 76%. Median disease-free survival was not reached. With a median follow-up of 10.5 months, 28 patients (49%) received allogeneic stem cell transplantation (HSCT) in first complete remission (CR). Centralized multicolour flow cytometry minimal residual disease (MFC-MRD) assessment was planned during the phase 2, part 2 of the study (confirmatory cohort) where the lower effective dose of VEN (400 mg/day) was administered in association with FLAI. Here we report results from early time-points (TPs) MRD analysis with the aim of identify the most informative TPs for MRD assessment and prognostic correlations. Methods: Erythrocyte-lysed whole bone marrow (BM) samples obtained at diagnosis from patients enrolled in the confirmatory cohort were centralized and analysed with a broad panel of monoclonal antibodies to identify the leukemia-associated phenotype (LAIP) which was used to track residual leukemic cells during follow-up. Eight color flow cytometry analysis was performed at pre-defined TPs (TP1: post-induction I, TP2: post induction II/consolidation I, following TPs: post consolidation/pre-transplantation) (FACSCantoII; BD Facs Diva Software V6.1.3). A positive flow MRD was defined by the presence of no less than 10 clustered leukemic cells/10^4 total events. Enrollment closed on January 2023. Collection and analysis of later TPs is ongoing. Results: Sixty-seven patients from 11 centers were enrolled in the phase 2, part 2. Risk stratification according to ELN 2017 was intermediate in 46% of patients and high risk in 54%. Fifty-eight/67 patients (87%) obtained CR after induction I. In the centralized MRD analysis, 170 samples has been collected and analysed so far (60 baseline samples, 110 MRD samples). Seven patients lacking baseline sample for LAIP identification were excluded from the analysis. TP1 was available in 57/59 patient achieving CR (97%), and TP2 was available in 29 patients, so far. MFC-MRD negativity was obtained in 31/57 (54%) at TP1 (post V-FLAI, Fig. 1). An increase in MFC-MRD negativity rate was observed at TP2 (post Induction II or consolidation I) with 20 MFC-MRD negative patients/29 available samples (69%, Fig. 1). Thirteen/110 follow up samples (8%), albeit resulting MRD negative, were considered inadequate for the analysis due to haemodilution, 9 from TP1 and 4 from TP2 (Fig. 1). TP1 and TP2 MRD assessment were scheduled at day 28 of Induction I and Induction II/consolidation, respectively. However, in most cases, delayed haematological recovery was observed after V-FLAI, thus resulting in suboptimal samples for MRD evaluation. Conclusions: Preliminary results from centralized MRD analysis confirm that the combination therapy is able to induce high-quality remissions with a very high percentage of MFC-MRD negativity in a difficult cohort of patients, with a higher percentage of MFC-MRD-negative after the completion of the second course of therapy. Delayed haematological recovery may impact on reliability of MRD assessment due to hypocellular and regenerative marrow samples, suggesting that in those cases MRD analysis should be postponed. Correlation with survival will be performed as the data collection will be complete.

Real-World Effectiveness and Safety Outcomes of Acalabrutinib Treatment By Line of Therapy in Patients with Chronic Lymphocytic Leukemia and/or Small Lymphocytic Lymphoma

Background: Acalabrutinib is a second-generation Bruton tyrosine kinase inhibitor (BTKi) approved by the Food and Drug Administration for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Data from phase 3, randomized, controlled trials of acalabrutinib, as monotherapy or in combination with obinutuzumab, in patients with treatment-naive (TN) and relapsed/refractory (R/R) CLL with long-term follow-up, including ELEVATE-TN, ELEVATE-RR, and ASCEND, have demonstrated sustained improvement vs comparators in progression-free survival and overall survival (OS) with cardiovascular (CV) and bleeding events consistent with previous reports (Sharman et al. J Clin Oncol. 2021; Byrd et al. J Clin Oncol. 2021; Ghia et al. Blood. 2022). As real-world evidence of the acalabrutinib effectiveness and safety profile is limited in CLL/SLL patients, this study aimed to describe time to next treatment (TTNT), OS, and CV and bleeding events in patients receiving first-line (1L) and later-line (2L+) acalabrutinib for the treatment of CLL/SLL in the real-world setting. Methods: A retrospective, observational analysis was conducted utilizing the Optum Clinformatics © Data Mart claims and electronic medical record database to identify patients aged ≥18 years with TN or R/R CLL/SLL who initiated acalabrutinib in any line of therapy (LoT) on or after November 21, 2019 (FDA approval date for acalabrutinib). Patients with CLL/SLL were required to have ≥6 months of continuous enrollment in the Optum database system prior to acalabrutinib treatment initiation. Patients were followed until the earliest of last day of data availability, death, or end of study period (September 30, 2022). Treatment effectiveness was described as TTNT (time from acalabrutinib initiation to next LoT or death of any cause) and OS (time from acalabrutinib initiation to date of death from any cause or end of study period). The Kaplan-Meier (KM) method was used to estimate TTNT and OS. Patients who continued treatment at the last follow-up were censored. CV and bleeding events were assessed in all patients who initiated acalabrutinib. All outcomes were evaluated in patients who received 1L or 2L+ acalabrutinib therapy. Results: A total of 530 patients were identified and included in the analysis. Of these patients, 63% (n=334) received 1L acalabrutinib and 37% (n=196) received 2L+ acalabrutinib. At acalabrutinib initiation, the mean age was 72.8 years in the 1L cohort and 74.2 years in the 2L+ cohort; 61.7% (121/196) of patients treated with 2L+ acalabrutinib had prior BTKi therapy prior to acalabrutinib initiation (ibrutinib, n=120; zanubrutinib, n=1). Distributions of gender and race were similar between the cohorts. At baseline, 18.1%, 75.3%, and 16.0% of patients had atrial fibrillation/flutter, hypertension, and bleeding episodes, respectively. With a median follow-up of 8.9 months in the 1L cohort and 12.4 months in the 2L+ cohort, the median TTNT and OS were not reached in either cohort. At 18 months, the proportion of patients remaining on treatment was 82% in the 1L cohort and 78% in the 2L+ cohort ( Figure 1). Of the patients that progressed, the median TTNT was 4.0 months in the 1L cohort (n=33) and 4.2 months in the 2L cohort (n=31). The 18-month OS rate was 90% and 85% for the 1L and 2L+ cohorts, respectively ( Figure 2). After initiation of acalabrutinib treatment, the incidence rates of atrial fibrillation/flutter, hypertension, and bleeding events were 2.7%, 8.9%, and 2.7% of patients in the 1L cohort and 7.4%, 2.4%, and 3.3% of patients in the 2L+ cohort, respectively, who had no history of these events prior to treatment with acalabrutinib. Conclusions: This is the first study demonstrating real-world effectiveness (OS and TTNT) and safety data of acalabrutinib treatment in first-line and later-line therapy. While clinical trial and clinical practice settings may differ, overall, the survival findings in this study were similar to those of acalabrutinib trials. The observed incidence rates of CV and bleeding events were not inconsistent with those observed in published acalabrutinib trials.

Frail and Pre-Frail Older Adults with Acute Myeloid Leukemia Have Inferior Survival Due to Higher Rates of Disease-Related Deaths

Introduction: The intensity of initial remission-inducing therapy for patients with newly diagnosed acute myeloid leukemia (AML) may be high (anthracycline and cytarabine-based), intermediate (venetoclax combinations), or low (single hypomethylating agent or targeted therapy). In older adults, it is important to consider “fitness” when selecting initial therapy. Current methods to determine “fitness” in AML include subjective measures such as physician assessment (“clinician gestalt, CG”) semi-subjective measures such Eastern Cooperative Oncology Group (ECOG) or Karnofsky performance status (KPS), and those based on clinical comorbidity data like the hematopoietic cell transplantation-comorbidity index (HCT-CI). Geriatric assessments in older adults with cancer may improve therapy selection and decision-making, but whether unfit patients have better outcomes with lower intensity compared to higher intensity therapies is unknown. Freid's Frailty Phenotype (FP) combines subjective (self-reported exhaustion, weight loss >5%, activity level) and objective (4-meter walk speed and grip strength) measures to categorize patients into fit, pre-frail, and frail. We hypothesized that being frail by FP is associated with higher overall mortality (OM) and inferior overall survival (OS) and may inform decision-making for older adults. Methods: Eighty-fivepatients 60 years or older admitted to the Hospital of the University of Pennsylvania at the time of AML diagnosis or electively admitted for AML chemotherapy initiation were prospectively enrolled from September, 2018 to May, 2023 on an IRB approved study. FP, HCT-CI, KPS, ECOG, gait speed, and recorded CG (fit or unfit) were performed prior to initiation of disease-directed therapy. Results: Themedian age of the cohort was 71 (range60-91). Patients in our cohort had high-risk disease features: 64% were adverse risk by European LeukemiaNet (ELN) 2017 with 73% of patients harboring mutations associated with clonal hematopoiesis of indeterminate potential (CHIP) (Table 1). 39% of patients received IC, 52% received HMA/ven, 6% received HMA alone or targeted therapy, and 2% received best supportive care. By FP, 18% of patients were fit, 38% were pre-frail, and 45% were frail. Higher ECOG, KPS, CG, and HCT-CI were associated with frail phenotypes (Table 1). For the entire population, 60-day and 100-day OM rates were 18% and 33%, respectively. For fit, pre-frail, and frail patients 60-day OM was 7%, 13%, and 24% and 100-day OM was 13%, 22%, and 42%, respectively. Two-year OS was 65% for patients aged 60-69 years old and 15% for patients ≥70 years old (p=0.002). FP was significantly associated with OS (Figure 1; p=0.0474): 2-year OS was 57%, 42%, and 21% in fit, pre-frail, and frail patients, respectively. Of the individual components of FP, self-reported exhaustion and slower gait speed were both associated with inferior OS (p=0.0015 and p=0.0005). Neither activity level, (p=.0864), weight loss (p=0.1988), or grip strength (p= 0.7136) were associated with OS. Of the total population 19% went on to hematopoietic cell transplant (HCT) with 8% of frail patients receiving HCT compared to 27% of fit and 28% of pre-frail patients. ECOG, HCT-CI, CG, and gait speed ≤8 meters/sec were all significantly associated with OS, but KPS was not. The 6-month OS for frail patients receiving IC was 75% compared with 49.7% for those receiving HMA/Ven, although not significant due to small sample size. Cause of death was leukemia-related for 40% of fit patients, 76% of pre-frail patients, 77% of frail patients. Conclusions: FP was associated with a doubling of early mortality and inferior 2-year OS. Pre-frail and frail patients had increased disease-related deaths. This work supports that most geriatric assessments, including FP and clinician intuition, can be utilized to risk-stratify newly diagnosed older adults with AML. Future work is needed to evaluate whether we can integrate geriatric assessments, such as individual components of FP or gait speed, with molecular features to improve risk stratification of older adults with AML. Given frailty's association with disease-related deaths, further study is warranted to determine whether this is due to adverse disease biology or whether frail patients are undertreated.

Epidemiology and survival outcomes of HIV-associated cervical cancer in Nigeria.

Invasive cervical cancer (ICC) is an HIV-associated cancer that is preventable and precancerous stages including early ICC stages could be detected through screening offering opportunities for treatment and cure. The high incidence in women living with HIV and late presentation often at advanced stages of ICC with limited treatment facilities often result in early mortality. We sought to compare the epidemiologic characteristics and survival differences in HIV status of ICC patients in Nigeria. We conducted a cohort study at two federal academic hospital-based research sites in Jos University Teaching Hospital, and Lagos University Teaching Hospital Nigeria, between March 2018 and September 2022. We enrolled women with histologically confirmed ICC with known HIV status, and FIGO staging as part of the United States of America's National Institutes of Health/National Cancer Institute funded project titled 'Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria'. The primary outcome was all-cause mortality with assessment of overall survival (OS) and time to death after ICC diagnosis. OS distribution was estimated using the method of Kaplan-Meier and compared between groups using the log-rank test. A total of 239 women with confirmed ICC were enrolled and included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC +), and 47 (19.7%) were HIV-positive (HIV +/ICC +). The HIV +/ICC + patients were younger with median age 46 (IQR: 40-51) years compared to 57 (IQR: 45-66) among HIV-/ICC + (P < 0.001). Squamous cell carcinoma was the commonest histopathologic variant in 80.4% of ICC diagnosis, moderately differentiated tumor grade in 68.1% in both groups. HIV +/ICC + diagnosis was at FIGO advanced stages in 64.9% compared to 47.9% in HIV-/ICC +. The HIV-/ICC + women had better OS compared to HIV +/ICC + participants (p = 0.018), with 12-month OS 84.1% (95%CI 75-90%) and 67.6% (95%CI 42-84%) respectively. ICC is diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis at advanced stages in women living with HIV could partly explain the differences in overall survival.

Real-world prostate-specific antigen reduction and survival outcomes of metastatic hormone-sensitive prostate cancer patients treated with apalutamide: An observational, retrospective, and multicentre study.

Backgroundetastatic hormone-sensitive prostate cancer (mHSPC) treatment has changed drastically during the last years with the emergence of androgen receptor–targeted agents (ARTAs). ARTA combined with androgen deprivation therapy has demonstrated better oncological and survival outcomes in these patients. However, the optimal choice among different ARTAs remains uncertain due to their analogous efficacy. ObjectivesThe objective of this study was to describe prostate-specific antigen (PSA) response and oncological outcomes of patients with mHSPC treated with apalutamide. Material and methodsMedical records from three different hospitals in Spain were used to conduct this study. Patients diagnosed with mHSPC and under apalutamide treatment were included between March 2021 and January 2023. Data regarding PSA response, overall survival (OS), and radiographic progression-free survival (rPFS) were collected and stratified by metastasis volume, timing, and stating. Results193 patients were included; 34.2% of patients were de novo mHSPC, and the majority was classified as m1b. The 18-month OS and rPFS were 92.5% and 88.9%, respectively. Patients with PSA levels ≤0.2 ng/ml showcased an 18-month OS rate of 98.7%, contrasting with 65.3% for those with PSA >0.2 ng/ml. Similar trends emerged for rPFS (97.4% and 53.7%, respectively). When differentiating between low-volume and high-volume metastasis, the OS rate stood at 98.4% and 80.7%, respectively, while the rPFS rates were 93% and 81.6%, respectively. No significant differences were found between groups stratified by metastasis timing. ConclusionThis real-world study on patients with mHSPC treated with apalutamide plus androgen deprivation therapy revealed robust oncological outcomes, aligning with the emerging evidence. The study's hallmark finding highlights the significance of rapid and deep PSA response as a predictor of improved oncological and survival outcomes.

Chemoradiotherapy Combined with Immunotherapy in Stage III Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Efficacy and Safety Outcomes

Background: Since the success of the PACIFIC trial, durvalumab has become the clear standard of care for many patients with stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CRT). However, the duration of immune consolidation and the efficacy and safety of different immune agents remain unclear. We conducted a systematic review of relevant studies. Methods: We searched all the relevant studies in PubMed, Embase, and Cochrane Library databases. We also reviewed abstracts of relevant conferences to prevent omissions. The meta-analysis was performed using Stata version 16.0. Results: CRT combined with immunotherapy can improve progression-free survival (PFS) (hazard rate [HR]: 0.60, 95% confidence interval [CI, 0.55–0.60) and overall survival (OS) (HR: 0.59, 95% CI, 0.53–0.66) compared with no immunotherapy. The pooled 24-month PFS and 24-month OS rates were 48.1% (95% CI, 43.5–52.7%) and 71.3% (95% CI, 67.3–75.2%), respectively. Subgroup analysis showed that 24-month OS rates were 60.7% (95% CI, 51.0–70.3%) and 77.4% (95% CI, 73.2–81.7%) at 1 year and 2 years of immune consolidation, respectively. The pooled 1-year completion rate for immune consolidation was 35.6% (95% CI, 31.3–39.8%). The pooled rate of pneumonitis for all grades was 41.7% (95% CI, 31.9–51.9%). The pooled rate of pneumonitis ≥ grade 3 was 6.7% (95% CI, 5.0–8.5%). The incidence of pneumonitis ≥ grade 3 after 1 year of immunotherapy is 4.8% (95% CI, 3.1–6.5%). The incidence of pneumonitis ≥ grade 3 after 2 years of immunotherapy is 5.1% (95% CI, 2.9–7.3%). Conclusions: Prolonging the duration of immunotherapy consolidation increases survival benefits in patients with stage III NSCLC without causing higher side effects. Older patients, due to high incidence of pneumonia and low immunotherapy completion rate, have less survival benefit.

Efficacy and safety of utidelone for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer who have failed standard second-line treatment: A phase 2 clinical trial (BG01-1801)

BackgroundChemotherapy remains the standard-of-care for many patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC), but acquired resistance presents challenges. The aim of this open-label, multicenter phase 2 clinical trial was to determine the efficacy and safety of utidelone, a novel genetically engineered epothilone analog and microtubule-stabilizing agent, as a third- or later-line treatment for locally advanced or metastatic NSCLC. MethodsPatients who had failed standard second-line treatment (including platinum-containing chemotherapy or targeted therapy) received utidelone (40 mg/m2 via intravenous injection daily, day 1–5) every 21 days. The primary endpoint was the objective response rate (ORR). Secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. ResultsFrom March 12, 2019 to January 18, 2021, 26 pretreated patients with locally advanced or metastatic NSCLC (100% of patients had received prior platinum and 65.4% patients had received prior taxane treatment) were enrolled (80.8% of patients had adenocarcinoma). At baseline, nine (34.6%) patients had received second-line treatment, 10 (38.5%) patients had received third-line treatment, and seven (26.9%) patients had received fourth- or later-line treatment. By the data cut-off date of August 10, 2021, the median follow-up was 7.49 months (range, 1.4–26.7 months). The ORR was 15.4% (95% confidence interval [CI], 4.4%–34.9%) in the intention-to-treat (ITT) cohort (N = 26) and 19.0% (95% CI, 5.4%–41.9%) in the per-protocol (PP) cohort (N = 21). The disease control rate was 69.2% (95% CI, 48.2%–85.7%) and 81.0% (95% CI, 58.1%–94.6%) in the ITT and PP cohorts, respectively. The median DoR was 4.1 months (95% CI, 3.1–5.1 months) in the ITT cohort. The median PFS was 4.37 months (95% CI, 2.50–5.29 months) in the ITT cohort and 4.37 months (95% CI, 2.50–9.76 months) in the PP cohort. The median OS was not reached, and the 12-month OS rate was 69% (95% CI, 45.1%–84.1%). Grade 3/4 treatment-emergent adverse events occurred in 38.5% of patients, and the most common was peripheral neuropathy (23.1%, all Grade 3), which was manageable with dose modifications. ConclusionsIn this clinical trial, utidelone showed promising efficacy and had a manageable safety profile. Further clinical studies are warranted to confirm its role in NSCLC treatment. Trial registrationNo.NCT03693547; https://classic.clinicaltrials.gov.

Combination Therapy of Bland Transarterial Embolization and Microwave Ablation for Hepatocellular Carcinoma within the Milan Criteria Leads to Significantly Higher Overall Survival.

A comparison of the combination therapy consisting of microwave ablation (MWA) after bland lipiodol-based transarterial embolization (TAE) with MWA alone in the treatment of hepatocellular carcinoma (HCC) within the Milan criteria. Forty-nine patients in the TAE-MWA group (12 women and 37 men; mean age: 63.3 ± 9.6 years) with 55 tumors and 63 patients in the MWA group (18 women and 45 men; mean age: 65.9 ± 10.5 years) with 67 tumors were retrospectively enrolled in this study. For the investigation of treatment protocols based upon both safety and efficacy, patients' cases were analyzed with regard to complications, local tumor progression (LTP), intrahepatic distant recurrence (IDR), overall survival (OS), and progression-free survival (PFS). There were no cases of major complications in either group. The LTP rate was 5.5% in the MWA-TAE group and 7.5% in the MWA group (p = 0.73). The rate of IDR was 42.9% in the MWA-TAE group and 52.4% in the MWA group (p = 0.42). The 12-, 24-, and 36-month OS rates starting at the date of tumor diagnosis were 97.7%, 85.1%, and 78.8% in the TAE-MWA group, and 91.9%, 71.4%, and 59.8% in the MWA group, respectively (p = 0.004). The 6-, 12-, and 24-month PFS rates were 76.5%, 55%, and 44.6% in the TAE-MWA group, and 74.6%, 49.2%, and 29.6% in the MWA group, respectively (p = 0.18). The combination therapy of TAE-MWA was significantly superior to MWA monotherapy according to OS in treating HCC within the Milan criteria.

The impact of clinical and translational research on the quality of life during the metastatic colorectal cancer patient journey.

The journey of metastatic colorectal cancer patients is complex and challenging, requiring coordination and collaboration between multiple healthcare providers. Understanding patients' needs, fears, feelings, concerns, and behaviors is essential for providing individualized patient-centered care. In recent years, mCRC patients have experienced improvements in clinical outcomes, from 16 months of overall survival to 32 months, thanks to research. However, there is still room for improvement, and integrating clinical and translational research into routine practice can help patients benefit from treatments and techniques that would not be an option. In the Journey of mCRC patients, living well with cancer and quality of life becomes a priority given the outcomes of the disease. Patient reported outcomes (PRO) and Patient Reported Outcome Measures (PROMs) are becoming therefore new estimands in Oncology. Patient advocates represent important figures in this process by prioritizing issues and research questions; evaluating research designs and the performance of the research; the analysis and interpretation of data; and how results are disseminated. Multidisciplinary Tumor Boards and shared decision-making is essential for designing treatment strategies for individual patients. Quality of Life is often prioritized only when it comes to refractory advanced disease and end-of-life care, but it has to be integrated from the beginning, as the emotional impact of diagnosis leads to a vulnerable situation where patients' needs and preferences can be easily overseen. First-line treatment will be chosen among more treatment options than subsequent lines, with longer progression-free survival and a bigger impact on the outcomes. Practicing patient-centered care and optimizing first-line treatment for colorectal cancer patients requires a comprehensive understanding of patient experience and treatment outcomes, which can guide clinical practice and inform regulatory decisions for the benefit of patients.

Repeated Stereotactic Radiotherapy for Local Brain Metastases Failure or Distant Brain Recurrent: A Retrospective Study of 184 Patients.

The main advantages of stereotactic radiotherapy (SRT) are to delay whole-brain radiotherapy (WBRT) and to deliver ablative doses. Despite this efficacy, the risk of distant brain metastases (BM) one year after SRT ranges from 26% to 77% and 20 to 40% of patients required salvage treatment. The role and consequences of reirradiation remain unclear, particularly in terms of survival. The objective was to study overall survival (OS) and neurological death-free survival (NDFS) and to specify the prognostic factors of long-term survival. we retrospectively reviewed the data of patients treated between 2010 and 2020 with at least two courses of SRT without previous WBRT. In total, 184 patients were treated for 915 BMs with two-to-six SRT sessions. Additional SRT sessions were provided for local (5.6%) or distant (94.4%) BM recurrence. The median number of BMs treated per SRT was one with a median of four BMs in total. The mean time between the two SRT sessions was 8.9 months (95%CI 7.7-10.1) and there was no significant difference in the delay between the two sessions. The 6-, 12- and 24-month NDFS rates were 97%, 82% and 52%, respectively. The 6-, 12- and 24-month OS rates were 91%, 70% and 38%, respectively. OS was statistically related to the number of SRT sessions (HR = 0.48; p < 0.01), recursive partitioning analysis (HR = 1.84; p = 0.01), salvage WBRT (HR = 0.48; p = 0.01) and brain metastasis velocity (high: HR = 13.83; p < 0.01; intermediate: HR = 4.93; p < 0.01). Lung cancer and melanoma were associated with a lower NDFS compared to breast cancer. A low KPS, a low number of SRT sessions, synchronous extracerebral metastases, synchronous BMs, extracerebral progression at SRT1, a high BMV grade, no WBRT and local recurrence were also associated with a lower NDFS. A high KPS at SRT1 and low BMV grade are prognostic factors for better OS, regardless of the number of BM recurrence events.

Treatment with trastuzumab deruxtecan in patients with HER2-positive breast cancer and brain metastases and/or leptomeningeal disease (ROSET-BM)

Therapeutic options for breast cancer patients with brain metastases (BM)/leptomeningeal carcinomatosis (LMC) are limited. Here, we report on the effectiveness and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2-positive breast cancer patients with BM. Data were analyzed for 104 patients administered T-DXd. Overall response rate (ORR), progression-free survival (PFS), overall survival (OS), intracranial (IC)-ORR, and IC-PFS were evaluated. ORR by investigator assessment was 55.7% (total population). Median PFS was 16.1 months; 12-month OS rate was 74.9% (total population). Median time-to-treatment failure was 9.7 months. In 51 patients with BM imaging, IC-ORR and median IC-PFS by independent central review were 62.7% and 16.1 months, respectively. In 19 LMC patients, 12-month PFS and OS rates were 60.7% and 87.1%, respectively. T-DXd showed effectiveness regarding IC-ORR, IC-PFS, PFS, and OS in breast cancer patients with BM/active BM, and sustained systemic and central nervous system disease control in LMC patients.Trial Registration: UMIN000044995.