Refractory Status Research Articles

Indirect comparison of linvoseltamab versus teclistamab for triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM).

7560 Background: No head-to-head clinical trials have compared effectiveness of anti-BCMA×CD3 bispecific antibodies for TCE RRMM. This analysis compared efficacy of linvoseltamab vs teclistamab via an unanchored matching-adjusted indirect comparison (MAIC). Methods: A MAIC was deemed feasible after excluding 10 patients (pts) with prior BCMA antibody–drug conjugate exposure from LINKER-MM1 (linvoseltamab) to match MajesTEC-1 (teclistamab) criteria. Pt-level data from LINKER-MM1 (107 pts receiving 200 mg in Phase 1/2, data cut-off [DCO] 9/2023, median follow-up 11.1 months [mos]) and published data from MajesTEC-1’s efficacy population (150 pts, DCO 11/2021, median follow-up 9.8 mos) were analyzed. LINKER-MM1 pts were weighted to match key baseline characteristics in MajesTEC-1 (cytogenetic risk, age, refractory status, ISS stage, ECOG score, extramedullary disease/plasmacytoma status) selected via a prespecified algorithm (Kumar et al., 2023). Objective response rate (ORR), very good partial response or better (≥VGPR), complete response or better (≥CR), and minimal residual disease (MRD) negativity (- [at 10-5 threshold]) rates, duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were compared. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were reported before and after matching; a sensitivity analysis included all LINKER-MM1 200 mg pts (n=117). Results: Effective sample size for linvoseltamab was 82 after matching and baseline characteristics were balanced with MajesTEC-1. Before and after matching, linvoseltamab exhibited higher ORR, ≥VGPR, ≥CR, and MRD(-) rates, with significant differences in ≥CR. Linvoseltamab had significantly longer PFS and a trend toward longer OS and DOR (Table). Sensitivity analysis results were similar. Conclusions: The results suggest potentially greater efficacy for linvoseltamab vs teclistamab for all outcomes, highlighting its potential as a highly effective treatment option for TCE RRMM. [Table: see text]

Comparing Phenotyping, Gene Expression, and Function of T Lymphocytes before Mobilization Chemotherapy Versus after Stem Cell Harvesting in Patients with B Cell Lymphoma and Multiple Myeloma

Chimeric Antigen Receptor T cell (CAR-T) therapy is an effective treatment for relapsed and refractory hematological diseases. However, a significant medical unmet need persists, particularly for patients at the relapse and refractory (R/R) status, who often experience leukopenia or lymphopenia during lymphocyte collection. This limitation poses considerable challenges to the successful implementation of CAR-T treatment, primarily due to the impaired function of T cells resulting from multiple lines of treatment and disease progression. As a consequence, the quality of the CAR-T cell product may be compromised. Before introducing CAR-T therapy, most patients with B cell lymphoma or multiple myeloma (MM) experienced mobilization chemotherapy and high-dose granulocyte colony-stimulating factor (G-CSF) administration for stem cell harvesting, followed by autologous stem cell transplantation as a salvage or consolidation treatment. Given that the procedure of lymphocyte collection for CAR T cell manufacturing is quite similar to stem cell harvesting, it becomes reasonable to explore the possibility of collecting lymphocytes immediately after the stem cell harvesting process. The advantage of this strategy is that patients are typically in a healthier condition with better T cell function compared to their status during R/R status. However, the effects of mobilization chemotherapy and high-dose G-CSF on T lymphocytes remain inadequately understood. To assess the feasibility of lymphocyte collection, it is essential to delve into the function of T lymphocytes at two critical time points: before mobilization chemotherapy compared to after stem cell harvesting. In this study, we recruited 19 patients with B cell lymphoma or MM. Paired peripheral blood samples were obtained before administering mobilization chemotherapy and after stem cell harvesting. Flow cytometry analysis using CCR7 and CD45RA markers was applied to classify T cell subsets, including T naive or T stem cell-like (TN/SCM, CCR7+/CD45RA+), T central memory (TCM, CCR7+/CD45RA-), T effector memory (TEM, CCR7-/C5RA-), and T effector (Teff, CCR7-/CD45RA+) (Figure A). The data indicated no significant difference in T cell phenotype between pre-mobilization chemotherapy and after stem cell harvesting. CD4and PD-1 expression were also analyzed and showed no significant difference between the two time points. To gain further insights, we performed RNA sequencing on 3 paired samples from patients with large B cell lymphoma (UPN#3, UPN#11, UPN#16). Through our observations, we noticed that these 3 paired samples could be clustered into 2 groups based on differential gene expression (Figure B), which corresponds to pre-mobilization chemotherapy versus post-stem cell harvesting status. Our findings strongly indicate that T cells at the pre-mobilization chemotherapy status exhibit significant differences in gene expression compared to those at the post-stem cell harvesting status. Specifically, T cells from post-stem cell harvesting show significantly higher expression of NIBANI, ALOX5AP, and GLUL compared to those from pre-mobilization. NIBANI plays a vital role in down-regulating apoptosis by interacting with the MDM2/p53/Bcl2/Bax pathway, promoting cell survival under stress-dependent conditions. GLUL is responsible for glutamine synthetase, and glutamine is an important source of biosynthetic precursors in active T cells. On the other hand, T cells from pre-mobilization show higher expression of TOX, DUSP4, and TGFBR3 compared to those from post-stem cell harvesting. TOX is a transcription factor involved in T cell exhaustion and senescence, while DUSP4 expression is associated with defective TCR signaling and accelerated T cell senescence. Our data indicate that the proportion of T naive or T stem cell-like phenotypes remains unchanged after mobilization chemotherapy and G-CSF injections during stem cell harvesting. RNA sequencing data further reveal that T cells at the post-stem cell harvesting status are associated with down-regulated apoptosis, favorable survival and activation, and reduced exhaustion and senescence compared to those at the pre-mobilization stage. This study suggests that instead of collecting lymphocytes during relapse or refractory status, collecting them right after stem cell harvesting may be a viable alternative.

Isatuximab Plus Pomalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM) in Real-Life Context in France: IMAGE Subgroup Analysis Based on Prior Lines of Therapy and Refractory Status in Anti-CD38-Naïve Population

Introduction: Isatuximab, a CD38 monoclonal antibody (mAb), targets a specific CD38 epitope to induce myeloma cell death. Based on the results of the Phase 3 ICARIA-MM study, isatuximab (Isa) plus pomalidomide (P) and dexamethasone (d; Isa-Pd) is approved in adult patients (pts) with relapsed/refractory multiple myeloma (RRMM) who have received ≥2 prior therapies. Prior to Isa-Pd regulatory approval, Isa was available in France under early access programs (EAPs). IMAGE is a non-interventional, retrospective cohort study of pts treated with Isa-Pd under the French EAPs. In the IMAGE overall effectiveness population (median follow-up 14.2 months [mo]), median progression-free survival (mPFS) was 12.4 mo; overall response rate (ORR) was 46.3%; 27.9% of pts achieved a very good partial response (VGPR) and best response was VGPR for 60.3% of pts. In the current myeloma landscape, not all pts with RRMM have received a prior anti-CD38 mAb, particularly where access is difficult; thus, the real-world effectiveness of Isa in daratumumab (dara)-naïve pts needs to be assessed in light of the Phase 3 APOLLO and ICARIA-MM trials investigating dara-Pd and Isa-Pd in dara-naïve populations. Effectiveness results from the IMAGE subgroup analysis of dara-exposed and -refractory pts have been presented previously. Here, we describe results for dara-naïve pts based on prior lines of therapy (LOT) and lenalidomide (len)-refractory status. Methods: Data were collected from medical records of adult pts with RRMM who received ≥1 dose of Isa under the EAPs from 29 Jul 2019-1 Sep 2020. The effectiveness analysis was restricted to pts with ≥1 year of follow-up after Isa initiation. PFS was defined as the time from Isa-Pd initiation to date of disease progression or death. VGPR was defined as a ≥90% reduction in serum or urine M-protein, or in the difference between involved and non-involved free light chain. The description of adverse events (AEs; verbatim) was recorded as a reason for treatment temporary or permanent discontinuation or dose reduction. Data were recorded per the subject's medical file. No specific grading was performed. Results: The safety population included 299 pts who received ≥1 Isa dose under the EAPs; of these, 294 received ≥1 Isa dose and met all inclusion/exclusion criteria, thus comprising the effectiveness population. Within the overall effectiveness population, 216 (73.5%) pts were dara-naïve; among them, 13.4%, 58.8%, and 27.8% received 1, 2, and ≥3 prior LOT, respectively; 72.2% were len-refractory (median 2 prior LOT); and 54.2% were len-refractory at last prior LOT. At a median follow-up of 14.2 mo, mPFS (95% CI) in dara-naïve pts was not reached (NR; 14.6-NR), 15.0 mo (10.6-NR), and 14.8 mo (7.6-NR) with 1, 2, and ≥3 prior LOT, respectively; 13.2 mo (9.0-18.6) in those refractory to len; and 13.2 (9.0-NR) in those refractory to len at last prior LOT. ORR (of which, VGPR) was 41.4% (17.2%), 52.0% (34.6%), and 50.0% (31.7%) in pts with 1, 2, and ≥3 prior LOT, respectively; 49.4% (29.5%) in len-refractory pts; and 50.4% (29.9%) in len-refractory at last prior LOT pts (Table). At least 1 AE was reported in 53 (24.4%) pts in the dara-naïve safety population (n=217): 7 (24.1%), 32 (25.2%), and 14 (23.0%) in the 1, 2, and ≥3 prior LOT subgroups, respectively; 41 (26.1%) in the len-refractory subgroup; and 32 (27.4%) in the len-refractory at last prior LOT subgroup. AEs led to permanent Isa discontinuation in 3 (2.4%) pts with 2 prior LOT; 3 (1.9%) len-refractory pts; and 2 (1.7%) len-refractory at last prior LOT pts. The most common AEs were blood and lymphatic system disorders, occurring in 39 (18.0%) pts. Infections and infestations were reported in 2 (0.9%) pts: 1 had received 1 prior LOT and 1 had 2 prior LOT; both pts were len-refractory at last prior LOT. Conclusions: In the dara-naïve populations from APOLLO (dara-Pd) and ICARIA-MM (Isa-Pd), mPFS was 12.4 and 11.1 mo, respectively. This subgroup analysis of IMAGE provides real-world evidence of Isa effectiveness in dara-naïve subgroups: Isa-Pd demonstrated a high mPFS of 16.6 mo in dara-naïve pts and meaningful mPFS at first and subsequent relapse, including in difficult-to-treat len-refractory pts; mPFS was generally comparable to that of the overall effectiveness population. No new safety signals were observed compared with ICARIA-MM. However, the incidence of some AEs like infections was low, possibly due to the retrospective nature of the study. Funding: Sanofi.

Clinical Outcomes in Real-World Patients (RW) with Triple-Class Exposed (TCE) Relapsed/Refractory Multiple Myeloma (RRMM): A Retrospective Study Using Electronic Health Records from Flatiron Health and COTA Vantage Databases

Introduction: With rapid treatment advances in multiple myeloma (MM), more patients receive the 3 main classes of MM treatments (immunomodulatory imide drug [IMiD] agents, proteasome inhibitors [PIs], and anti-CD38 monoclonal antibodies [mAbs]) in earlier lines of therapy and become TCE. This is a prerequisite for subsequent treatment with some novel therapies eg, anti-B-cell maturation antigen (BCMA) agents. Published evidence of RW clinical outcomes in patients with TCE MM is scarce in the evolving RRMM treatment landscape. The objective of this study was to assess RW clinical outcomes in patients with TCE RRMM who received treatment post-TCE. Methods: In this observational study, we analyzed de-identified patient data derived from electronic health records (EHRs) from 2 key United States (US) MM longitudinal databases (Flatiron Health MM [FHMM] and COTA Vantage MM [CVMM]). We identified patients who became TCE between November 2015 and March 2021 and received a subsequent treatment post-TCE; the earliest available end date of the 3rd treatment class was considered the date patients became TCE. The start date of the 1st treatment post-TCE (index treatment) was defined as the index date. We analyzed patient demographics, disease characteristics, prior treatment exposure, refractory status, and index treatments patterns/classes. Clinical endpoints assessed were response rates (overall and complete), overall survival (OS), progression-free survival (PFS), and time to progression (TTP). Results: The FHMM and CVMM databases included 1,319 and 1,118 TCE patients, respectively, of whom 897 and 795 received an index treatment post-TCE. Median (range) follow-up for patients who received an index treatment was 18.1 (0.1-82.0) and 15.5 (0.03-72.3) months for FHMM and CVMM cohorts, respectively. Median age for both RW cohorts was 68 years, more than half of patients were men and the majority were White. Patients received a median of 3 lines of prior treatment (range, 1-14 and 1-12 for FHMM and CVMM cohorts, respectively). In both RW cohorts, >75% of patients who received an index treatment were triple-class refractory and approximately 10% were penta-refractory, having received treatment with 2 IMiD agents, 2 PIs, and an anti-CD38 mAb. Approximately 67% and 79% of patients in the FHMM and CVMM cohorts, respectively, had ECOG performance status 0 or 1. Approximately 54% and 61% had received prior stem cell transplantation. IMiD agents either alone or in combination with a PI and/or anti-CD38 mAb constituted the main regimens for index-treated patients. In the CVMM cohort, the overall and complete response rates were 15.2% and 1.7%, respectively; response data were not available in the FHMM cohort. Median OS (22.3 and 20.4 months), median PFS (4.8 and 4.9 months), and median TTP (5.9 and 5.9 months) were comparable for both FHMM and CVMM cohorts. Conclusions: In this observational cohort study of 2 US RW EHR databases, patients became TCE with a median of 3 prior lines of therapy. Post-TCE, most patients with RRMM still received the same 3 treatment classes with poor response and survival outcomes on their treatments. Despite advances in MM management, this study highlights the need for more efficacious novel treatments for patients with TCE MM and serves as a RW benchmark in the literature for appraising emerging data from novel agents in patients with RRMM.

Allogeneic hematopoetic stem cell transplant for patients with refractory T-Cell lymphomas.

Allogeneic stem cell transplantation (allo-SCT) may have a curative potential due to the graft versus lymphoma effect. In this study, we aimed to compare transplant outcomes between refractory-T-NHL (ref-NHL) and Chemosensitive-T-NHL (CS-T-NHL). We retrospectively reviewed the records of 26 ref-NHL and 29 CS-T-NHL consecutive patients who underwent allo-SCT at our center and compared the transplant outcomes between the groups. All patients were heavily pretreated with 27% of patients relapsing post-auto-SCT and two patients in the ref-T-NHL post-allo-SCT. Patients were transplanted mainly from unrelated donors. There were no differences in leucocytes and platelet engraftment between the two groups. At 3 years, the relapse incidence was 34% in Ref-TNHL and 19% in CS-TNHL (p = .33), with non-relapse mortality rates of 28% and 22%, respectively (p = .52). Female patients and those with a previous auto-SCT had lower relapse incidence (p = .045, p = .003). The 3-year overall survival was 39% in Ref-TNHL and 56% in CS-TNHL (p = .15). Trends for improved progression-free survival (PFS) and graft-versus-host disease relapse-free survival (GRFS) were observed in the CS-TNHL group (PFS: 60% vs. 30%, p = .075; GRFS: 38% vs. 21%, p = .1). Acknowledging the retrospective nature of our study, our results indicate that allo-SCT has a curative potential in patients with T-NHL even in refractory status.

The treatment of refractory periorbital dermatitis.

Refractory periorbital dermatitis has a chronic course with exacerbations leading to discomfort and cosmetic issues, yet characterization of treatment options is limited. The objective was to present comprehensive demographic data and medical management of a series of patients with refractory periorbital dermatitis. Retrospective review identified patients treated at a single institution from January 2010 to August 2020. Descriptive analyses were performed. Demographic data and treatment history were reviewed and data including medication, use, date of use and discontinued use, reason for discontinuation (if applicable), refractory status, formulation, concentration, and dose frequency were extracted. Descriptive analyses. Forty-five patients were included. The average age at first diagnosis was 60.3 years (sd 14.9). 82.2% were women and 84.4% identified as Caucasian. Triamcinolone cream was most frequently used followed by tobramycin-dexamethasone, tacrolimus, and neomycin-polymyxin-dexamethasone. Less than 30% of patients on triamcinolone were refractory. 13.3% of patients used topical hydrocortisone, with over 80% of these patients experiencing refractory episodes of persistent irritation and erythema. Most patients were refractory during initial use or the first recurrence of periorbital dermatitis flare. By better characterizing the diverse treatment regimens in a unique subset of refractory patients, we hope to better inform potential courses of medical management for periorbital dermatitis.

Efficacy of CLAE Chemotherapy Regimen Followed by Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed/Refractory Acute Leukemia

To observe the efficacy and safety of CLAE intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with relapsed/refractory acute leukemia (R/R AL). CLAE regimen [cladribine 5 mg/(m2·d), d 1-5; cytarabine 1.5 g/(m2·d), d 1-5; etoposide 100 mg/(m2·d), d 3-5] followed by allo-HSCT was used to treat 3 R/R AL patients. The patients received CLAE chemotherapy in relapsed or refractory status and underwent bone marrow puncture to judge myelodysplastic state. After an interval of 3 to 5 days, followed by preconditioning regimen for allo-HSCT [fludarabine 30 mg/(m2·d), d -7 to d -3; busulfan 0.8 mg/kg q6h, d -6 to d -3 or d -5 to d -2. If the bone marrow hyperplasia was not active and the blasts were less than 10%, busulfan should be used for 3 days. If the bone marrow hyperplasia was active and the blasts were more than 10%, busulfan should be used for 4 days]. Cyclosporin A, mycophenolate mofetil and short-term methotrexate were used for graft-versus-host disease (GVHD) prevention. After transplantation, the status of minimal residual disease (MRD) and bone marrow chimerism were regularly monitored in all 3 patients, and demethylation drugs or dasatinib were used to prevent recurrence 3 months after transplantation. 2 patients with t(11;19) translocation and relapse/refractory acute myeloid leukemia recurred within 6 months after induction of remission, and received intensive chemotherapy with CLAE regimen followed by haploidentical allo-HSCT and unrelated donor allo-HSCT, respectively. The two patients both relapsed 6 months after transplantation, then achieved complete remission by donor lymphocyte infusion, interferon, interleukin-2 and other methods, and disease-free survival was 2 years after transplantation. The other patient was chronic myelogenous leukemia who developed acute lymphoblastic leukemia during oral administration of tyrosine kinase inhibitor, accompanied by T315I and E255K mutations in ABL1 kinase region and additional chromosomal abnormalities. After morphological remission by induction chemotherapy, central nervous system leukemia was complicated. Intensive chemotherapy with CLAE regimen followed by sibling allo-HSCT was performed in the positive state of MRD. The patient relapsed 3 months after transplantation, and achieved remission after chimeric antigen receptor T-cell (CAR-T) therapy, however, he died 5 months after transplantation because of severe cytokine release syndrome (CRS) and GVHD. CLAE regimen followed by allo-HSCT may be an effective salvage treatment option for R/R AL patients to prolong the overall survival.

Abstract 3398: Clinical use of next-generation sequencing panel in pediatric oncology patients

Abstract Background: Next-generation sequencing (NGS) technology is gradually expanding in cancer diagnosis and therapeutic decision-making. However, reports on the clinical performance and utility of pan-cancer NGS panel in pediatric patients are still lacking. Methods: We analyzed the patients who underwent brain tumor or pan-cancer NGS panel sequencing at Seoul National University Children’s Hospital. DNA-based NGS panel testing was started in April 2018, and RNA panel was added from January 2022. Single nucleotide variants/small insertions and deletions (SNV/INDEL), fusion, copy number alteration (CNA), microsatellite instability (MSI) and tumor mutational burden (TMB) were evaluated. Results: A total of 140 patients were analyzed between August 2018 and March 2022. The median age at diagnosis was 8.5 (range 0.0-31.8) years. The diagnoses were CNS tumors in 56 (40.0%), sarcoma in 45 (32.1%), other solid tumors in 36 (25.7%) and histiocytosis in 3 (2.1%) patients. At the time of NGS testing, 115 patients (75.2%) were newly diagnosed and 38 patients (24.8%) were in relapsed or refractory status. In all patients, 85.7% had at least one pathogenic or likely pathogenic variant. Diagnosis was refined or changed in five patients (3.6%) after the NGS panel results were reported. Oncogenic gene fusions were discovered in 45 (32.1%) patients. EWSR1, BRAF, NTRK and RET-related fusions were the most common. Frequent SNV/INDEL included BRAF, CTNNB1 and TP53 mutations. Common CNA were CDKN2A and CDKN2B loss, MYCN amplification, CCND3 amplification and PTEN loss. Nine (6.4%) patients were identified with germline alteration, additionally. No patient had MSI, and two patients had high TMB. Fifteen patients (10.7%) were enrolled in clinical trials or compassionate use program according to molecular profiling (DAY101 [BRAF inhibitor] in 3, selpercatinib in 3, palbociclib in 2, olaparib in 2, alectinib in 1, repotrectinib in 1, larotrectinib in 1, atezolizumab in 1 and erdafitinib in 1). Two (1.4%), one (0.7%) and one (0.7%) patients received vemurafenib, larotrectinib, and pembrolizumab with non-reimbursement. Best responses included two complete response (1 high grade glioma [HGG] and 1 renal cell carcinoma), five partial responses (2 low grade glioma, 1 HGG, 1 Langerhans cell histiocytosis, and 1 papillary thyroid carcinoma), two stable disease and six progressive diseases. Four patients were not evaluable due to short duration of drug administration. One-year progression free survival and overall survival was 54.5% and 52.7%, respectively. Conclusions: Application of NGS panel in pediatric cancer aid in diagnosis, treatment decision, clinical trial enrollment and germline risk determination. Although there are not many cases linked with molecular target-based therapy, it is leading to clinical benefits in pediatric patients and more understanding genomic profiling of pediatric cancer. Citation Format: Jung Yoon Choi, Hyun Jin Park, Bo Kyung Kim, Kyung Taek Hong, Jaemoon Koh, Sung-Hye Park, Jeong Mo Bae, Hongseok Yun, Hyoung Jin Kang. Clinical use of next-generation sequencing panel in pediatric oncology patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3398.

Zanubrutinib Demonstrates Superior Progression-Free Survival (PFS) Compared with Ibrutinib for Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (R/R CLL/SLL): Results from Final Analysis of ALPINE Randomized Phase 3 Study

Introduction: CLL/SLL is usually characterized by consecutive relapses and response to therapy ultimately dictates survival. While ibrutinib, a first-generation Bruton tyrosine kinase inhibitor (BTKi), has become standard therapy, it has well-described off-target effects that can limit use. Compared with ibrutinib, zanubrutinib, a next-generation BTKi, provides improved BTK occupancy across disease-relevant tissues with greater kinase selectivity. In a randomized phase 3 study (ALPINE; NCT03734016), zanubrutinib was compared head-to-head with ibrutinib as treatment for R/R CLL/SLL. At predefined response analyses, zanubrutinib demonstrated superior overall response rate (ORR); data from the predefined final PFS analysis are reported here. Methods: Patients (pts) with R/R CLL/SLL who had received ≥1 prior therapy and had measurable disease were randomized 1:1 to receive zanubrutinib or ibrutinib until disease progression or unacceptable toxicity. Stratification was based on age, refractory status, geographical region, and del(17p)/TP53 mutation status. As the primary endpoint of ORR was superior with zanubrutinib, the key secondary efficacy endpoint of PFS was tested for noninferiority under hierarchical testing when 205 PFS events were observed. If PFS noninferiority between zanubrutinib and ibrutinib was demonstrated, superiority of zanubrutinib vs ibrutinib could be tested and claimed if the 2-sided P-value was <.04996. Other endpoints included overall survival (OS), ORR including PR with lymphocytosis (PR-L) or better, and safety parameters including atrial fibrillation/flutter. Results: Pts (N=652) from 15 countries were randomized to receive zanubrutinib (n=327) or ibrutinib (n=325). Demographic and disease characteristics were balanced between zanubrutinib and ibrutinib arms (age ≥65 yrs [61.5 vs 61.5%]; male [65.1 vs 71.4%]; unmutated IGHV [73.1 vs 73.5%]; del(17p) [13.8 vs 15.4%]; TP53 mutated without del(17p) [9.2 vs 7.7%]). Across the study population, median age was 67 and 68 yrs, respectively; in both arms, median prior lines of therapy was 1. With a median follow-up of 29.6 mo (data cutoff, 8 Aug 2022), zanubrutinib PFS, assessed by independent review committee (PFSIRC), was superior to ibrutinib in the ITT population (HR: 0.65 [95% CI, 0.49-0.86]; 2-sided P=.0024 [Fig 1]); identical statistical values were reported when assessed by investigator (INV). Median PFSIRC was 35.0 mo (95% CI, 33.2-44.3) for ibrutinib-treated pts but not reached for zanubrutinib-treated pts. In a predefined subgroup of pts with del(17p)/TP53 mutation, longer PFSIRC was demonstrated with zanubrutinib than ibrutinib (Fig 2). PFS, regardless of IRC or INV assessment, consistently favored zanubrutinib across other major predefined subgroups, including IGHV status. Compared with ibrutinib, zanubrutinib had a higher ORRIRC (86.2 vs 75.7%, nominal 2-sided P=.0007), with a rate of PR-L or better of 91.7% vs 83.1% (nominal 2-sided P=.001). Treatment discontinuation rate was lower with zanubrutinib (26.3%) vs ibrutinib (41.2%) with most due to AEs (16.2 vs 22.8%) or progressive disease (7.3 vs 12.9%); discontinuation rates due to cardiac disorders were 0.3% vs 4.3%. Rates of grade ≥3 AEs (67.3 vs 70.4%), serious AEs (42.0% vs 50.0%), dose interruption (50.0% vs 56.8%), and dose reduction (12.3 vs 17.0%) were also lower with zanubrutinib vs ibrutinib. Rate of atrial fibrillation/flutter was lower with zanubrutinib compared with ibrutinib (5.2% vs 13.3%); rates of other AEs of special interest were similar between treatments. There were no grade 5 AEs due to cardiac disorders with zanubrutinib vs 6 (1.9%) with ibrutinib. Overall, 48 (14.7%) pts treated with zanubrutinib and 60 (18.5%) treated with ibrutinib had died (OS HR: 0.76 [95% CI, 0.51-1.11]). Conclusions: As ALPINE is the first study to demonstrate PFS superiority in a head-to-head comparison of BTK inhibitors, zanubrutinib has now proven superiority to ibrutinib in both ORR and PFS in pts with R/R CLL/SLL. Efficacy benefits with zanubrutinib were observed across all major subgroups, including high-risk pts. Zanubrutinib had a favorable safety profile compared with ibrutinib, with a lower rate of treatment discontinuation and fewer cardiac disorder events, including fewer cardiac events leading to death. These data suggest zanubrutinib is more efficacious and better tolerated than ibrutinib as treatment for R/R CLL/SLL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Isatuximab Plus Pomalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma in Real-Life Context in France: IMAGE Subgroup Analysis Based on Prior Lines of Therapy and Refractory Status

Introduction: Isatuximab (Isa) plus pomalidomide (P) and dexamethasone (d; Isa-Pd) is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have received ≥2 prior therapies, based on the Phase 3 ICARIA-MM study (NCT02990338). Prior to Isa-Pd regulatory approval, Isa was available in France under early access programs (EAPs). In the non-interventional, retrospective IMAGE study, we analyzed the progression-free survival (PFS) and safety among French pts with RRMM treated with Isa-Pd under the EAPs. Here, we report results from the interim subgroup analysis of the IMAGE study based on prior lines of therapy (LOT) and refractory status. Methods: The IMAGE study was conducted based on medical records of adult patients with RRMM who received ≥1 dose of Isa under the EAPs. The analysis of effectiveness endpoints was restricted to patients with ≥1 year of follow-up after Isa initiation. PFS was defined as the time from start of Isa-Pd to date of disease progression or death. Refractoriness was defined per IMWG criteria. Adverse events (AEs) were not graded for severity. Verbatim terms for AEs were coded using the Medical Dictionary for Regulatory Activities. Results: Across 62 study sites in France, 299 patients who had received ≥1 Isa dose under the EAPs from 29 Jul 2019 -1 Sep 2020 were included in the safety population; the effectiveness population included 294 pts who met all inclusion/exclusion criteria. In contrast to ICARIA-MM, the IMAGE study included daratumumab-refractory patients and patients who had received only 1 prior LOT. In the effectiveness population, 10.2%, 49.0%, 40.8% received 1, 2, and ≥3 prior LOT, respectively; 96.3% had lenalidomide; 26.5% had daratumumab; 73.1% were lenalidomide-refractory; and 19.1% were daratumumab-refractory. At a median follow-up of 14.2 months (mo), median PFS (mPFS) of the overall effectiveness population was 12.4 (95% CI 9.0-15.0) mo (Table) with a median 2 prior LOT; this is similar to that reported for daratumumab plus Pd (12.4 mo) in the APOLLO study and for Isa-Pd (11.1 mo) in the ICARIA-MM study, where patients received a median of 2 and 3 prior LOT, respectively. Median PFS was not reached (NR; 95% CI 9.6-NR), 13.6 (95% CI 10.2-NR), and 7.6 (95% CI 4.4-11.8) mo among patients with 1, 2, and ≥3 prior LOT, respectively; 9.0 (95% CI 6.4-12.4) mo in lenalidomide-refractory subgroup; and 10.6 (95% CI 6.8-15.0) mo in lenalidomide-refractory at last prior LOT (Table). Within the lenalidomide-refractory subgroup, mPFS (95% CI) was NR (6.8-NR), 10.6 (6.8-NR), and 5.0 (3.2-7.8) mo with 1, 2, and ≥3 prior LOT, respectively. Among daratumumab-naïve patients, median PFS (95% CI) was 16.6 (13.2-NR) mo. Patients exposed to daratumumab had a median washout period of 6.5 mo between last daratumumab injection and Isa initiation. Patients exposed and refractory to daratumumab had a mPFS of 3.0 (2.4-4.8) mo with a median washout period of 4.0 mo, while patients who were exposed to daratumumab but were not refractory had a mPFS of 8.4 (95% CI 2.8-NR) mo and a median washout period of 9.5 mo. At least 1 AE was reported in 8 (26.7%), 38 (26.4%), and 33 (26.4%) patients in 1, 2, and ≥3 prior LOT subgroups; 60 (27.5%) in lenalidomide-refractory subgroup; and 43 (30.7%) in lenalidomide-refractory at last prior LOT subgroup. AEs led to permanent Isa discontinuation in 3 (2.1%) patients with 2 prior LOT, 1 (0.8%) patient with ≥3 prior LOT, 4 (1.8%) patients in lenalidomide-refractory subgroup, and 3 (2.1%) patients in lenalidomide-refractory at last prior LOT subgroup. Conclusions: In this subgroup analysis of the IMAGE study based on prior LOT and refractory status, Isa-Pd demonstrated meaningful mPFS with a manageable safety profile at first and second relapse and in the difficult-to-treat lenalidomide-refractory subgroups. Importantly, a high mPFS of 16.6 mo was reported for daratumumab-naïve patients. In the APOLLO and ICARIA-MM trials investigating daratumumab plus Pd and Isa-Pd in a daratumumab-naïve population, mPFS was 12.4 and 11.1 mo respectively. The IMAGE study shows daratumumab-refractory patients do not respond well to Isa-Pd. However, as PFS outcomes were favorable in patients who were exposed to but not daratumumab-refractory, anti-CD38 antibody sequencing in successive therapies may be a good alternative in real-world practice when patients may be exposed to daratumumab but not refractory. Funding: Sanofi. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Patterns and Patient Outcomes in Relapsed/Refractory Multiple Myeloma (RRMM) Stratified By Exposure to Lenalidomide or Anti-CD38 Therapy and Double-Class Refractory Status: A Retrospective Electronic Health Record Database Study

Introduction: While new treatments have been introduced for multiple myeloma, patients typically experience repeated relapses and progress through complex treatment pathways involving multiple lines of treatment (LOT). It remains unclear to what extent novel therapies are being utilized in treatment regimens for patients with RRMM. This study assessed treatment patterns and outcomes in patients with RRMM to better understand the current treatment landscape, unmet needs, and challenges in real-world clinical settings. Methods: This longitudinal retrospective cohort study utilized the COTA de-identified database, which contains data from curated electronic health records of partnered US healthcare centers (index date Nov 16, 2015 to Apr 15, 2022). Study investigators identified adult patients with active RRMM who had received ≥1 prior LOT. In addition, subcohorts were created based on patients' prior exposure and refractory status: 1) prior exposure to lenalidomide (LEN-E); 2) refractory to both a proteasome inhibitor (PI) and an immunomodulatory therapy (double-class refractory [DCR]); 3) prior exposure to an anti-CD38 agent (daratumumab or isatuximab; CD38-E); 4) no prior exposure to an anti-CD38 agent (CD38-N). Demographics, clinical characteristics, and treatment patterns were analyzed descriptively. Time-to-event outcomes including (but not limited to) progression-free survival (PFS), duration of therapy (DOT), and time to next therapy (TTNT) were evaluated with Kaplan-Meier survival analysis. Results: In total, 1368 patients with ≥1 prior LOT were identified in the overall 2L+ population, comprising 4 overlapping subcohorts: LEN-E: 1305, DCR: 649, CD38-E: 717, CD38-N: 963; 57% were treated in an academic setting. Median age at index was 66.5 (range 27.7-96.2) yrs and 55% were male; baseline characteristics were similar across cohorts (Table). Mean time from diagnosis to index LOT was 18.5 mo (SD: 27.0). Prior to index LOT, 19.9% of patients received autologous stem cell therapy, and 25.7% of those with known ISS staging (n=997) had stage 3 disease; 43.9% had ≥1 high-risk cytogenetic features. In the overall 2L+ population at index LOT, the most common therapies were treatment regimens containing anti-CD38 agents (monotherapy or combination; 20.8%), other PI/immunomodulatory combinations (13.2%), triplets containing carfilzomib and dexamethasone (DEX) (12.9%), triplet therapy with bortezomib (BOR)/LEN/DEX (12.4%), and stem cell transplant (12.4%). In general, at later LOTs, there was a decline in use of doublets (2L: 17.0%, 3L: 13.6%, 4L: 9.6%; 5L: 11.1%) and triplets (2L: 29.3%, 3L: 15.0%, 4L: 15.4%, 5L: 11.8%), while a greater proportion of patients received anti-CD38 agents (3L: 39.5%, 4L: 42.9%, 5L: 43.9%). Treatment sequences varied greatly across cohorts. Following index LOT, 63.5% of 2L+ patients began a subsequent LOT (LOT+1). Across the subcohorts, rates of beginning LOT+1 ranged from 57.3% (CD38-E) to 69.8% (DCR) (Table 1). Given their prior exposure to anti-CD38 therapy prior to index LOT, a notably high proportion of patients in the CD38-E cohort (N=717) received an anti-CD38 agent at index LOT (49.8%), LOT+1 (28.2%), and/or LOT+2 (18.1%). Overall, median DOT was short across overall 2L+ patients and sub-cohorts, and generally remained constant across LOTs (Figure). Median PFS and TTNT varied between cohorts, with shorter durations in DCR and CD38-E cohorts. In the CD38-E patients, TTNT and PFS declined markedly across patients indexed on increasing LOTs from 2L to 6L+ (TTNT: 19.7 mo to 6.3 mo; PFS: 19.2 mo to 5.3 mo), with similar patterns seen in the LEN-E and DCR cohorts. Conclusions: Despite development of novel therapies for MM, patients continue to receive recycled therapies at later LOTs, as demonstrated by the high rate of retreatment with prior therapies, including anti-CD38 agents. Standard of care varies by LOT and prior treatment exposure or refractory status, with no dominant regimens across cohorts. TTNT and PFS remain suboptimal across all cohorts, especially in later LOTs. These findings support the need for increased uptake of new treatments with novel mechanisms of action earlier in the patient journey, including at first relapse. This approach may provide a broader range of treatment regimens and offer additional benefits to patients with RRMM. Funding: GSK (217353) Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Bridging Therapy (BT) of Patients with Relapsed or Refractory (r/r) Large B-Cell Lymphoma (LBCL) Treated with Chimeric Antigen Receptor (CAR) T-Cell Therapy: A Systematic Literature Review (SLR) and Meta-Analysis

Objectives: Using BT with commercially available CAR T-cell therapy for treatment of r/r LBCL is at the discretion of treating physicians. With emerging real-world data on CAR T-cell therapy, we conducted an SLR to understand the patterns of BT use in real-world settings and to investigate its association with effectiveness and safety outcomes. Methods: We systematically searched EMBASE, MEDLINE, and 15 conferences through April 1, 2022 for real-world observational studies describing patterns of BT use among adult patients receiving CAR T-cell therapy for r/r LBCL. In addition to data on the use of BT, the estimated effects of BT on clinical outcomes were also extracted. Weighted means were calculated using both fixed- and random-effects meta-analyses for use and type of BT, study location, and CAR T-cell product. The associations between use of BT and post-infusion overall and complete response rate (ORR and CR rate), progression-free survival (PFS), overall survival (OS), cytokine release syndrome (CRS), and neurotoxicity (NT) were assessed by meta-analyses of the reported effects of BT, with adjusted and unadjusted treatment effects analyzed separately. Results: The search identified 4,242 citations; 65 publications on 42 studies reporting on real-world use of BT were included in the evidence base, of which 32 publications on 25 studies reported on the associations between BT and clinical outcomes. No real-world study on lisocabtagene maraleucel was found at the time of the search. At baseline (apheresis or infusion), patients receiving axicabtagene ciloleucel (axi-cel) were younger compared with patients receiving tisagenlecleucel (tisa-cel) (weighted average of median age 59.5 years for axi-cel vs 62.6 years for tisa-cel), while more likely to have an International Prognostic Index (IPI) of ≥ 3 (51% for axi-cel vs 41% for tisa-cel), and more likely to have bulky disease (24% for axi-cel vs 16% for tisa-cel); sex, disease stage, double/triple hit, number of prior lines of therapy, prior history of autologous stem cell transplant, and refractory status were comparable between the two products. A shorter median time from leukapheresis to infusion (vein-to-vein time) for axi-cel was observed in both US- (weighted average 27.7 d for axi-cel vs 44.0 d for tisa-cel) and European-based studies (40.0 d for axi-cel vs 49.3 d for tisa-cel). On weighted average, 63% (95% confidence interval [CI] 53%-72%) of axi-cel recipients received BT compared with 80% (95% CI 72%-86%) of tisa-cel recipients (Table 1). Overall, use of BT was also more common in Europe (83%) than in the US (51%). Among patients who received BT, the most common type was chemo/chemoimmunotherapy (70% overall; 62% for axi-cel; 88% for tisa-cel) followed by steroids in the US (21% vs 12% in Europe) or radiation therapy in Europe (17% vs 17% in the US). Response to BT was seldomly reported and heterogeneous. Meta-analyses based on 7 available real-world cohorts (6 studies) that reported adjusted results on OS did not provide sufficient evidence to indicate an association between use of BT and OS (hazard ratio [HR] 1.20; 95% CI 0.76-1.89; Figure 1). Use of BT was also not associated with PFS based on adjusted results of 4 available cohorts (HR 1.28; 95% CI 0.91-1.80). Limited to unadjusted results only, no significant associations were found between use of BT and ORR (odds ratio [OR] 0.91; 95% CI 0.60-1.38), CR rate (OR 0.40; 95% CI 0.10-1.71), CRS of grade ≥ 3 (OR 0.98; 95% CI 0.54-1.76) or NE of grade ≥ 3 (OR 1.36; 95% CI 0.94-1.97). Conclusions: These findings provide a comprehensive picture of patterns of BT use in real-world settings, notably its more frequent use in Europe and among patients receiving tisa-cel. Despite the more frequent use of BT with tisa-cel, patients receiving tisa-cel did not appear to have more severe disease at baseline, suggesting that the shorter vein-to-vein time for axi-cel may have contributed to the reduced use of BT among its recipients. Given the use of BT could be heavily confounded by unknown factors that affect physicians’ decisions, the lack of adjusted analyses limit the conclusions that can be drawn on its association with clinical outcomes. Prospective studies evaluating the value of integrating BT with CAR T-cell therapy are warranted. JM and ZHH contributed equally. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CLL-115 First Interim Analysis of ALPINE Study: Results of a Phase 3 Randomized Study of Zanubrutinib vs Ibrutinib in Patients With Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

CLL/SLL treatment has been transformed with Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib. Zanubrutinib, a next-generation BTKi, was designed to maximize BTK occupancy and minimize toxicity. ALPINE (NCT03734016) is a global, randomized, phase 3 study of zanubrutinib versus ibrutinib in patients with R/R CLL/SLL; presented here is a pre-planned interim analysis conducted ~12 months after 415 patients enrolled between November 5, 2018, and December 20, 2019. Patients were randomized 1:1 to zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily) arms; stratification factors were age (<65 years vs ≥65 years), geographic region, refractory status, and del(17)p/TP53 mutation. Primary endpoint was investigator-assessed overall response rate (ORR) per 2008 IWCLL guidelines or Lugano criteria; the noninferiority of zanubrutinib-to-ibrutinib response ratio was evaluated at the noninferiority margin of 0.8558. If noninferiority was demonstrated, superiority of zanubrutinib versus ibrutinib in ORR was tested. Baseline characteristics (zanubrutinib versus ibrutinib): age ≥65 years: 62.3% versus 61.5%, male sex 68.6% versus 75%; >3 prior therapies: 7.2% versus 10.1%; del(17)p: 11.6% versus 12.5%; TP53 mutation without del(17)p: 8.2% versus 5.8%. With a median follow-up of 15 months, ORR was 78.3% versus 62.5% for zanubrutinib versus ibrutinib, respectively (2-sided P=0.0006, prespecified a=0.0099). ORR was higher for zanubrutinib in patients with del(11)q (83.6% vs 69.1%) and del(17)p (83.3% vs 53.8%); zanubrutinib had higher overall 12-month progression-free survival (PFS; 94.9% vs 84.0%) and overall survival (97.0% vs 92.7%). Significantly fewer patients had atrial fibrillation/flutter (AF) with zanubrutinib versus ibrutinib (2.5% vs 10.1%, 2-sided P=0.0014, prespecified a=0.0099). Zanubrutinib had lower rates of major bleeding (2.9% vs 3.9%), adverse events leading to discontinuation (7.8% vs 13.0%), and death (3.9% vs 5.8%). Zanubrutinib had a higher neutropenia rate (28.4% vs 21.7%) while grade ≥3 infections (12.7% vs 17.9%) were lower. In summary, this interim analysis showed zanubrutinib had a superior ORR, improved PFS, and lower AF rate compared to ibrutinib.

CLL-033 Is COVID-19 Infection a Trigger for Progression of CLL?

Introduction: COVID-19 diagnosed in chronic lymphocytic leukemia (CLL) could have a severe evolution with many complications. Chemo immunotherapy and immunological status could be the main causes of this evolution. The aim of this study was to check if COVID-19 could associate with a progression of CLL. Materials and Methods: The retrospective study included 40 CLL patients (33 male and 7 female) with a median age of 64.5 (95% CI for median: 59-67) who were admitted to the Hematology Department Colentina between March 2020- March 2022). These patients were diagnosed with COVID-19 by PCR test and were evaluated from 2020 to 2022. Results High count of leucocytes (WBC)- more than 50 × 1000/µL was identified in 15 patients (37.5%). Persistence of hyperleukocytosis after 1 month of evolution was identified in 10 patients, in 7 of them starting treatment was needed, all these patients were in the watch and wait for the group before the onset of COVID-19. Infection of SARS-Cov-2 diagnosed in CLL patients was associated with refractory status and progression of CLL during the follow-up period, a switch to another line of treatment was needed. Long COVID is defined as persistence long time for symptoms and the positivity of the PCR test was directly correlated with an immune deficit (r=0.37, p=0.01). Thrombotic complication developed by CLL patients during COVID-19 evolution was associated with vascular risk presence (diabetes mellitus, arterial hypertension, thrombosis history- stroke or myocardial infarction) –(r=0.61, p=0.0001). Unfavorable evolution was highly correlated with high severity of pneumonia/respiratory insufficiency and immune deficiency presence; the high count of WBC at the onset or during the first month of COVID-19 was not associated with a high risk of deceased. Conclusion COVID-19 could be a trigger for the progression of CLL. A strong analysis of the high cohort is needed. The immune deficit is involved in the severity of COVID-19 and the unfavorable evolution of the patients. Vascular risk presence in CLL patients is associated with thrombotic complication.

Impact on Outcome of Minimal Residual Disease after Hematopoietic Stem Cell Transplantation with Fludarabine, Amsacrine, and Cytosine Arabinoside-Busulfan Conditioning: A Retrospective Monocentric Study

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after conditioning with a sequential association of fludarabine, amsacrine, and cytosine arabinoside (FLAMSA) followed by a reduced-intensity conditioning regimen has emerged for patients with high-risk acute myeloid leukemia (AML), especially in refractory or relapsing patients. Here we aimed to address retrospectively the impact of pretransplantation minimal residual disease (MRD) by flow cytometry on the outcomes of high-risk AML patients who underwent allo-HSCT after sequential FLAMSA-busulfan (FLAMSA-Bu)-based conditioning regimens. We included 165 high-risk AML patients who underwent transplantation after FLAMSA-BU in this retrospective single-center "real life" study. All patients received in vivo T cell depletion with antithymocyte globulin (5 mg/kg). MRD detection was based on a leukemia-associated immunophenotype using the European LeukemiaNet recommendations, with a threshold of .1%. Univariate and multivariate analyses were performed using R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria). With a median follow-up of 4.0 years post-transplantation, the median overall survival (OS) was 54.9 months. Overall, 41 patients (24.8%) relapsed post-transplantation, with a resulting cumulative incidence of relapse (CIR) of 26.7% at 2 years and 34.0% at 5 years. Detectable MRD preceding allo-HSCT and refractory status were associated with worse median OS and CIR rates compared with patients without detectable MRD; however, OS was not significantly different between pre-HSCT MRD-positive and refractory patients (median, .7 year versus 2.0 years; P=.3). Conversely, pre-HSCT MRD negativity was associated with a reduced 2-year CIR. Neither European LeukemiaNet risk stratification nor age had a significant influence on OS. In the multivariate analysis, only pre-HSCT MRD positivity and lower conditioning regimen intensity were significantly associated with a poorer OS. The cumulative incidence of extensive chronic graft-versus-host disease at 2 years was 26.15%. The estimated nonrelapse mortality (NRM) of the entire cohort at 2 years was 23.1%, with age and unrelated donor identified as risk factors for higher NRM. Our data ahow that FLAMSA-Bu conditioning did not reverse the pejorative effect of detectable pre-HSCT MRD, suggesting that such patients should be offered alternative strategies before HSCT to reach deeper remission.

Neck Pain With Abdominal Distention in a Patient With Systemic Lupus Erythematosus

Question: A 13-year-old boy admitted for systemic lupus erythematosus (SLE) presented mild neck pain, throat pain, and abdominal distention. The SLE was diagnosed 6 months previously, and he received steroid pulse therapy, tacrolimus, and hydroxychloroquine for its treatment. Prolonged steroid therapy was required for his refractory status. Three months previously, he had an episode of right-sided cervical lymphadenitis caused by Staphylococcus aureus. He had no history of trauma. The patient had a good appetite and denied having symptoms such as dyspnea, cough, abdominal pain, nausea, vomiting, diarrhea, and bloody stool. A physical examination revealed right-sided neck pain with mild subcutaneous emphysema. No abnormalities were observed in his throat. Abdominal distention without tenderness was found. Laboratory tests were negative for elevated inflammatory markers, hemoconcentration, and lactic acidosis. Radiography demonstrated linear air leaks in the neck, multiple air leaks along the trachea, free air, and a curvilinear collection of gas within the bowel wall (Figures A and B). Given these physical and radiological findings, what is the most likely diagnosis? See the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Curbside Consult. Additional contrast computed tomography performed for a possible intestinal perforation found pneumomediastinum (Figures C and D), massive free air in the abdomen, and extensive air accumulation within a thickened bowel wall (Figures E, F, and G). Based on the mild clinical appearance and laboratory findings, pneumatosis cystoides intestinalis and pneumomediastinum without intestinal perforation were diagnosed. Careful observation with oxygen therapy, antibiotic administration, bowel rest, and total parenteral nutrition were begun, and the steroid dosage was gradually reduced. As a result, the patient recovered in 2 weeks without surgical intervention. Based on the clinical course and follow-up radiography and computed tomography findings, we concluded that his condition was idiopathic pneumatosis cystoides intestinalis with pneumomediastinum. Idiopathic pneumatosis cystoides intestinalis is characterized by the presence of gas within the intestinal submucosa or subserosa. The condition may be asymptomatic or present mild, nonspecific clinical manifestations, such as abdominal distention, discomfort, nausea, diarrhea, and anorexia, which may lead to an underdiagnosis of this condition.1Heng Y. Schuffler M.D. Haggitt R.C. et al.Pneumatosis intestinalis: a review.Am J Gastroenterol. 1995; 90: 1747-1758PubMed Google Scholar The risk factors of pneumatosis cystoides intestinalis have not been definitively identified, but prolonged administration of steroids or immunosuppressive agents is thought to be involved in its onset.2Mizoguchi F. Nanki T. Miyasaka N. Pneumatosis cystoides intestinalis following lupus enteritis and peritonitis.Intern Med. 2008; 47: 1267-1271Crossref PubMed Scopus (23) Google Scholar Atrophy of submucosal tissue caused by prolonged steroid therapy may also occur. Gastrointestinal involvement in SLE takes various forms,3Frittoli R.B. Vivaldo J.F. Costallat L.T.L. et al.Gastrointestinal involvement in systemic lupus erythematosus: a systematic review.J Transl Autoimmun. 2021; 4100106Crossref PubMed Scopus (12) Google Scholar making the correct diagnosis particularly important. The clinical presentations of our patient were not caused by complications of SLE because his clinical SLE activity was under control with prednisolone, tacrolimus, and hydroxychloroquine. The fact that reducing the prednisolone dosage did not exacerbate his condition corroborated our diagnosis. We herein described a case of massive pneumatosis cystoides intestinalis with pneumomediastinum accompanied by mild symptoms. Appropriately evaluating the symptoms, even when they are mild, is necessary in patients with prolonged steroid therapy.

PB2014: TECLISTAMAB VS SELINEXOR-DEXAMETHASONE IN PATIENTS WITH TRIPLE-CLASS EXPOSED RELAPSED/REFRACTORY MULTIPLE MYELOMA: A MATCHING-ADJUSTED INDIRECT COMPARISON

Background: Teclistamab, is a B-cell maturation antigen × CD3 bispecific antibody. MajesTEC-1 (NCT04557098), a single-arm, phase 1/2 study evaluating teclistamab in patients with RRMM who were exposed to at least 3 lines of therapy (LOT), comprising a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Though there is currently no standard of care for patients with triple-class exposed (TCE) RRMM, selinexor-dexamethasone (sel-dex) is a recently approved, novel therapeutic option. Aims: An unanchored matching-adjusted indirect comparison (MAIC) was conducted to compare efficacy results of patients treated with teclistamab in MajesTEC-1 with those treated with sel-dex in the single-arm, phase 2b STORM Part 2 study (NCT02336815). Methods: Individual patient-level data (IPD) collected from 150 patients treated with 1.5 mg/kg weekly teclistamab from MajesTEC-1 (Sep 7, 2021 data cut) and published summary-level data from 122 patients treated with sel-dex in the STORM Part 2 study were used in the unanchored MAIC. Eligibility criteria from STORM Part 2 (triple-class refractory, penta-exposed, and refractory to last LOT) were applied to patients in the MajesTEC-1 trial. The resulting IPD from 69 patients from the MajesTEC-1 trial were then weighted to match the aggregated baseline characteristics of patients from STORM Part 2. Baseline characteristics of prognostic significance were cytogenetic profile, presence of extramedullary disease, refractory status, revised International Staging System stage, and number of prior LOT; all were adjusted for in the analysis. Overall response rate (ORR), complete response or better (≥CR) rate, progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were estimated to compare efficacy between teclistamab and sel-dex. For binary endpoints (ORR and ≥CR rate), odds ratio (OR) and 95% confidence interval (CI), derived from a weighted logistic regression, were used to estimate relative effects of teclistamab vs sel-dex. A weighted Cox proportional hazards model was used to estimate time-to-event endpoints (PFS, OS, and DOR). Results: Baseline characteristics were balanced between the 2 cohorts. The effective sample size (ESS) of the MajesTEC-1 cohort was 37 after adjustment. Improved ORR (OR 3.14; 95% CI 1.48–6.69; P=0.0029), ≥CR rate (OR 16.3; 95% CI 3.5–77.1; P=0.0004), PFS (HR 0.58; 95% CI 0.30–1.11; P=0.1007), DOR (hazard ratio [HR] 0.04; 95% CI 0.01–0.10; P<0.0001), and OS (HR 0.52; 95% CI 0.28–0.95; P=0.0344) were observed in patients treated with teclistamab versus those treated with sel-dex. The majority of outcomes in favor of teclistamab were significant (P<0.05), despite a reduced ESS which limited power to detect statistically significant differences. Summary/Conclusion: Teclistamab significantly improved efficacy over sel-dex for all outcomes except PFS (though numerically in favor of teclistamab) in this MAIC. These findings highlight the potential of teclistamab as a highly effective treatment option for patients with TCE RRMM who received at least 3 prior LOT.

PB2013: TECLISTAMAB COMPARED WITH REAL-WORLD THERAPIES IN PATIENTS WITH TRIPLE-CLASS EXPOSED RELAPSED/REFRACTORY MULTIPLE MYELOMA

Background: Teclistamab is a B-cell maturation antigen × CD3 bispecific antibody that promotes T cell activation by redirecting CD3+ T cells, resulting in lysis of BCMA-expressing myeloma cells. MajesTEC-1 (NCT04557098) is an open-label, single-arm, phase 1/2 trial of teclistamab in patients with relapsed/refractory multiple myeloma (RRMM) who had received at least 3 prior lines of therapy (LOT) and were triple-class exposed (TCE) to a proteasome inhibitor, an anti-CD38 monoclonal antibody, and an immunomodulatory agent. Aims: Because MajesTEC-1 did not include a control arm, comparative effectiveness of teclistamab versus treatment regimens using an external control arm from a real-world database was evaluated. Methods: The external control arm was created using eligible patients in the nationwide Flatiron Health multiple myeloma database, which was derived from de-identified electronic health records. Patients comprising the external control arm had received ≥3 prior LOT, started a new LOT per physician’s choice after triple-class exposure between January 2011 and August 2021, and met key MajesTEC-1 eligibility criteria. Individual patient data were included from patients who had been treated with 1.5 mg/kg weekly teclistamab in the MajesTEC-1 at the Sep 7, 2021 clinical cutoff. Imbalances in baseline covariates of prognostic significance (refractory status, number of prior LOT, progression on last LOT, International Staging System stage, cytogenetic risk, time since diagnosis, age, and hemoglobin), were adjusted by using inverse probability of treatment weighting (IPTW). Progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) were outcomes of interest, and were analyzed as time-to-event data utilizing IPTW adjusted Kaplan-Meier estimates and a weighted Cox proportional hazards model. Several sensitivity analyses were also performed. Results: The two cohorts were comparable for baseline characteristics after IPTW. Teclistamab improved PFS (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.32–0.59; P<0.0001), TTNT (HR 0.42; 95% CI 0.31–0.58; P<0.0001), and OS (HR 0.73; 95% CI 0.48–1.09; P=0.13) compared with real-world treatments. Sensitivity analyses showed results were also consistent with these findings. Summary/Conclusion: In patients with TCE RRMM who received at least 3 prior LOT, teclistamab showed improved effectiveness for PFS, TTNT, and OS versus real-world treatments, highlighting the therapeutic potential of teclistamab for patients with RRMM.

P898: COMPARISON OF TECLISTAMAB WITH BELANTAMAB MAFODOTIN IN PATIENTS WITH TRIPLE-CLASS EXPOSED RELAPSED/REFRACTORY MULTIPLE MYELOMA USING MATCHING-ADJUSTED INDIRECT TREATMENT COMPARISON

Background: Treatment options are limited for patients with relapsed/refractory multiple myeloma (RRMM) who are triple-class exposed (TCE) to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies. While there is no standard of care for treatment of patients with TCE RRMM, belantamab mafodotin (belamaf) is a recently approved, novel therapeutic option. Teclistamab (tec; JNJ-64007957) is a B-cell maturation antigen × CD3 bispecific antibody currently being evaluated in the single-arm, phase 1/2 MajesTEC-1 study (NCT04557098) in patients with TCE RRMM who received ≥3 prior lines of therapy. Aims: Given the absence of a control arm in MajesTEC-1, the efficacy outcomes of patients treated with tec at the recommended phase 2 dose in MajesTEC-1 were compared with those treated with belamaf in the phase 2 DREAMM-2 study (NCT03525678). Methods: An unanchored matching-adjusted indirect comparison was conducted using individual patient-level data (IPD) from 150 patients treated with tec 1.5 mg/kg weekly in MajesTEC-1 (clinical cutoff of Sep 7, 2021), and published summary-level data from 97 patients treated with the approved dose of belamaf (2.5 mg/kg every 3 weeks) in DREAMM-2. After applying the DREAMM-2 eligibility criteria to patients from the intent-to-treat population of MajesTEC-1, IPD from MajesTEC-1 were weighted to match the aggregated DREAMM-2 baseline patient characteristics. Baseline characteristics of prognostic significance (such as cytogenetic profile, International Staging System stage, presence of extramedullary disease, number of prior lines of therapy, and refractory status) were adjusted for the analysis. Comparative efficacy of tec vs belamaf was estimated for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DOR), overall survival (OS), and progression-free survival (PFS). An odds ratio (OR) and 95% confidence interval (CI) derived from a weighted logistic regression analysis was used to compare the relative effects of tec vs belamaf for binary outcomes (ORR and ≥CR rate). A weighted Cox proportional hazards model was used to estimate time-to-event endpoints (DOR, OS, and PFS). Results: After adjustment, the effective sample size of the MajesTEC-1 cohort was 33. Baseline characteristics were balanced between MajesTEC-1 and DREAMM-2 after reweighting the MajesTEC-1 cohort. Tec-treated patients had improved outcomes compared with patients treated with belamaf: ORR (OR 2.05; 95% CI 0.92–4.57; P=0.0786), ≥CR rate (OR 2.13; 95% CI 0.80–5.65; P=0.1283), DOR (hazard ratio [HR] 0.19; 95% CI 0.05–0.73; P=0.0149), OS (HR 0.95; 95% CI 0.47–1.92; P=0.8897), and PFS (HR 0.63; 95% CI 0.34–1.15; P=0.1338). For most outcomes, the lack of statistical significance may be due to the reduced effective sample size following adjustment. Summary/Conclusion: In this comparative analysis, tec showed statistically improved DOR when compared with belamaf and numerically favorable results for other outcomes. This highlights the potential of tec as a treatment option for patients with TCE RRMM who received ≥3 prior lines of therapy.

Abstract 2630: Heterogeneity inducible tumor stem cells relate distant metastasis and the treatment resistance

Abstract Regarding metastatic potential of cancer cells and the refractory status, regulatory and epigenetic factors underlie the cancer treatment resistance by inducing cellular heterogeneity. Circulating tumor cells (CTCs) and their stemness are critical for metastases formation associated with poor survival rates. In colorectal cancer (CRC), several stem-cell markers, such as CD44v9 and LGR5, the positive cells cause intertumoral heterogeneity and promote refractory potential. However, the mastermind of the cells which is critical for the treatment resistance remains unknown. Here, we aimed to identify the mechanisms of the treatment resistance of the CRC by focusing on typical stem cells. We selected several stem cell-related genes such as pluripotency related genes, based on the expression profile analysis of CRC patients along with drug susceptibility assays using patient-derived organoids. Despite the small number of cancer stem cells, the single cell produced heterogeneous cell populations in vitro and in vivo, expressing various differentiation and stem biomarkers, and confirmed by the knockdown analysis. Single-cell trajectory analysis suggested that heterogeneous populations including cancer stem and some persister cells were derived from the stem cells following administration of anti-cancer drugs. Furthermore, the stem cells formed heterogeneous liver metastases at a high rate, and these unique cells were observed in the bloodstream of CRC patients. This present study unveils a mechanism of CRC treatment resistance and highlights the potential of stem marker-expressing cells as CTCs. Citation Format: Norikatsu Miyoshi, Shiki Fujino, Yuki Sekido, Tsuyoshi Hata, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, HIrofumi Yamamoto, Yuichiro Doki, Hidetoshi Eguchi. Heterogeneity inducible tumor stem cells relate distant metastasis and the treatment resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2630.