Higher Overall Response Rate Research Articles

Impact of losing adipose tissue on outcomes from PD-1/PD-L1 inhibitor monotherapy in non-small cell lung cancer.

BackgroundAdipose tissue induces inflammation, which desensitizes the efficacy of immunotherapy. However, several reports show that the therapeutic effect of programed cell death 1 (PD‐1)/programed death‐ligand 1 (PD‐L1) inhibitor(s) monotherapy is significantly better in obese patients. Therefore, the effect of adipose tissue on immunotherapy is unclear.MethodsIn this study, we retrospectively reviewed patients with advanced non‐small cell lung cancer (NSCLC) who received PD‐1/PD‐L1 inhibitor monotherapy between May 2016 and December 2018. We classified patients into total adipose tissue maintenance or loss groups according to adipose tissue change during the 6 months before treatment and compared the therapeutic effect of PD‐1/PD‐L1 inhibitors between these groups along with the presence or absence of cachexia, a poor prognostic factor.ResultsOf the 74 patients, 40 (54.1%) were cachexic. Among cachexic patients, we found no clear difference in the overall response rate (ORR) and progression‐free survival (PFS) between the total adipose tissue maintenance and loss group. However, among noncachexic patients, the total adipose tissue loss group had a higher ORR (64.7% vs. 23.5%, p < 0.05) and longer PFS (18.5 months vs. 2.86 months, p = 0.037) than the maintenance group.ConclusionsThis study showed that decreasing adipose tissue without cachexia might favor the therapeutic effects of immunotherapy.

Guideline for the treatment of chronic lymphocytic leukaemia

Guideline for the treatment of chronic lymphocytic leukaemia

Abstract P5-13-08: Identification of PD-L1+ status as a candidate predictive biomarker of response to talazoparib (TALA) in the phase 3 EMBRACA study

Abstract Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). In EMBRACA, the PARPi TALA improved progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P&amp;lt;0.001) vs chemotherapy (CT) in germline BRCA-mutated (gBRCAm) HER2− advanced breast cancer. BRCA1/2 deficiency is associated with elevated PD-L1 expression in ovarian cancers, and PARP inhibition has been associated with PD-L1 upregulation in nonclinical models (Stewart et al, Cancer Res 2018;78:6717-25). Little is known about the potential for PD-L1 expression to modulate sensitivity to PARPi monotherapy in the clinic. Recently, a neoadjuvant study of olaparib in unselected, primary triple-negative breast cancer (TNBC), demonstrated a significant correlation between PD-L1 expression (using the 22C3 antibody) and response to olaparib (Eikesdal et al, Ann Oncol 2021;32:240-9). In contrast, this EMBRACA analysis assessed the contribution of PD-L1 status to TALA sensitivity in a uniformly gBRCAm patient (pt) population. Methods: Available baseline tumor tissue blocks from 120 of 431 EMBRACA pts (28% of intent-to-treat) were sectioned and slides immunostained using SP142/Ventana anti-PD-L1 at HistoGeneX (Naperville, Illinois). PD-L1 immunohistochemistry (IHC) status was assessed as the proportion of tumor area occupied by PD-L1 stained immune cells (IC) of any intensity, with ≥1% defined as PD-L1+. The overall response rate (ORR), defined as unconfirmed complete or partial response (CR/PR), was assessed by investigators. PFS was assessed by an Independent Review Facility. Results: 92/120 (77%) tumors were evaluable for PD-L1 IHC status. Of these 92 evaluable tumors, 9/36 (25%) TNBC and 15/56 (27%) hormone receptor-positive (HR+) tumors were PD-L1+ (24/92, 26% combined TNBC and HR+). In the TALA arm, the ORR was similar for PD-L1+ and PD-L1− tumors for TNBC pts: 2/5 (40%) and 6/19 (32%), respectively. In contrast, the ORR was higher for PD-L1+ vs PD-L1− tumors for HR+ pts: 11/12 (92%) vs 12/31 (39%), exact P value=0.002 (for combined TNBC and HR+, 13/17 [76%] vs 18/50 [36%], P=0.005). For the CT arm, the limited numbers evaluable for both PD-L1 and response (n=25 total), with only one response, precluded similar analysis. Based on the imbalanced results in ORR according to PD-L1 status in pts with HR+ disease, Cox regression analysis was used to explore potential associations of PD-L1 status with PFS. In the TALA arm, median PFS was similar for TNBC independent of PD-L1 status (6.3 mo and 7.0 mo, respectively; HR [95% CI] 1.207 [0.371-3.929]). Median PFS was numerically longer for PD-L1+ vs PD-L1− for HR+ tumors; this difference was not significant (20.2 mo vs 9.2 mo; HR [95% CI] 1.154 [0.395-3.367]). In the CT arm, PD-L1 status was not associated with PFS, although the PD-L1 subgroups were small (For HR+: PD-L1+, n=3; PD-L1−, n=10). Conclusions: Based on these exploratory, retrospective subgroup analyses, PD-L1 positivity by SP142/Ventana was lower in EMBRACA than previously reported in TNBC using the same scoring algorithm: 24/92 (26%) vs 369/902 (41%) in IMpassion130 (Schmid et al, Lancet Oncol 2020;21:44-59). PD-L1+ status was associated with higher ORR in HR+ EMBRACA pts receiving TALA. Interestingly, the enhanced responsiveness for PD-L1+ was not associated with improved PFS, although this assessment is complicated by low pt numbers. Further research is warranted to explore the relationship between baseline tumor PD-L1 status and sensitivity to PARPi, particularly in light of ongoing clinical studies evaluating combinations of immunotherapy and PARPi. Citation Format: Hope S. Rugo, Joanne L. Blum, A. Douglas Laird, Sara A. Hurvitz, Johannes Ettl, Lida A. Mina, Kyung-Hun Lee, Anthony Gonçalves, Rinat Yerushalmi, Young-Hyuck Im, Miguel Martin, Louis Fehrenbacher, Henri H. Roché, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Wolfgang Eiermann, Jennifer K. Litton. Identification of PD-L1+ status as a candidate predictive biomarker of response to talazoparib (TALA) in the phase 3 EMBRACA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-08.

Safety and Efficacy Analysis of Selinexor-Based Treatment in Multiple Myeloma, a Meta-Analysis Based on Prospective Clinical Trials

Background: Selinexor (SEL) is an orally bioavailable, highly-selective, and slowly-reversible small molecule that inhibits Exportin 1. Preclinical studies showed that SEL had synergistic antimyeloma activity with glucocorticoids, proteasome inhibitors (PIs) and immunomodulators. The combination of selinexor and dexamethasone (DEX) has been approved in the United States for patients with penta-refractory multiple myeloma in July 2019. This meta-analysis aimed to investigate the safety and efficacy of selinexor based treatment in Multiple myeloma. Methods: We systematically searched the Medline (PubMed), Embase, Web of Science, Cochrane Central Register of Controlled Trials Library databases and ClinicalTrials.gov. Outcome measures of efficacy included overall response rate (ORR), clinical benefit rate (CBR), stringent complete response rate (sCR), complete response rate (CR), very good partial response (VGPR), partial response rate (PR), minimal response (MR), rate of stable disease (SDR), rate of progressive disease (PDR) and median progression-free survival (mPFS). Safety was evaluated by the incidences of all grade adverse events and Grade≥3 adverse events. The subgroup analysis was conducted to analyze the difference in different combination treatment regimens (SEL + DEX + PIs vs SEL + DEX). Results: We included six studies with 477 patients. The pooled ORR, CBR, sCR, CR, VGPR, PR, MR, SDR, and PDR were 43% (18–67%), 55% (32–78%), 5% (−2–13%), 7% (4–11%), 14% (5–24%), 23% (15–31%), 11% (8–14%), 26% (14–38%) and 14% (4–23%), respectively. SEL + DEX + PIs treatment had higher ORR (54 vs 24%, p = 0.01), CBR (66 vs 37%, p = 0.01), sCR (10 vs 2%, p = 0.0008), and VGPR (23 vs 5%, p < 0.00001) compared to SEL + DEX treatment, and lower PDR (4 vs 23%, p < 0.00001) and SDR (17 vs 37%, p = 0.0006). The pooled incidences of any grade and grade≥3 were 45 and 30% in hematological AEs, and in non-hematological AEs were 40 and 30%, respectively. The most common all grade (68%) and grade≥3 (54%) hematological AE were both thrombocytopenia. Fatigue was the most common all grade (62%) and grade≥3 (16%) non-hematological AE. Compared to SEL + DEX treatment, SEL + DEX + PIs treatment had lower incidences of hyponatremia (39 vs 12%, p < 0.00001), nausea (72 vs 52%, p < 0.00001), vomiting (41 vs 23%, p < 0.0001), and weight loss (42 vs 17%, p = 0.03) in all grade AEs. Meanwhile, SEL + DEX + PIs treatment had lower incidences of anemia (36 vs 16%, p = 0.02), fatigue (20 vs 13%, p = 0.04), hyponatremia (22 vs 5%, p < 0.0001) than SEL + DEX treatment in grade≥3 AEs. Conclusion: Our meta-analysis revealed that selinexor-based regimens could offer reasonable efficacy and tolerable adverse events in patients with multiple myeloma. SEL + DEX + PIs treatments had higher efficacy and lower toxicities than SEL + DEX.

The MAGNOLIA Trial: Zanubrutinib, a Next-Generation Bruton Tyrosine Kinase Inhibitor, Demonstrates Safety and Efficacy in Relapsed/Refractory Marginal Zone Lymphoma.

Marginal zone lymphoma (MZL) is an uncommon non-Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory (R/R) MZL. Patients with R/R MZL were enrolled in the phase II MAGNOLIA (BGB-3111-214) study. The primary endpoint was overall response rate (ORR) as determined by an independent review committee (IRC) based on the Lugano 2014 classification. Sixty-eight patients were enrolled. After a median follow-up of 15.7 months (range, 1.6 to 21.9 months), the IRC-assessed ORR was 68.2% and complete response (CR) was 25.8%. The ORR by investigator assessment was 74.2%, and the CR rate was 25.8%. The median duration of response (DOR) and median progression-free survival (PFS) by independent review was not reached. The IRC-assessed DOR rate at 12 months was 93.0%, and IRC-assessed PFS rate was 82.5% at both 12 and 15 months. Treatment was well tolerated with the majority of adverse events (AE) being grade 1 or 2. The most common AEs were diarrhea (22.1%), contusion (20.6%), and constipation (14.7%). Atrial fibrillation/flutter was reported in 2 patients; 1 patient had grade 3 hypertension. No patient experienced major hemorrhage. In total, 4 patients discontinued treatment due to AEs, none of which were considered treatment-related by the investigators. Zanubrutinib demonstrated high ORR and CR rate with durable disease control and a favorable safety profile in patients with R/R MZL.

A Phase I/II Study of Venetoclax in Combination with 5-Azacytidine in Treatment-Naïve and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

A Phase I/II Study of Venetoclax in Combination with 5-Azacytidine in Treatment-Naïve and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Phase 1/2 Trial of IL7/IL15-Expanded Bispecific LV20.19 CAR T-Cells for Relapsed, Refractory B-Cell Non-Hodgkin Lymphoma

Phase 1/2 Trial of IL7/IL15-Expanded Bispecific LV20.19 CAR T-Cells for Relapsed, Refractory B-Cell Non-Hodgkin Lymphoma

Once Weekly Oral Selinexor, Pomalidomide, and Dexamethasone in Relapsed Refractory Multiple Myeloma

Once Weekly Oral Selinexor, Pomalidomide, and Dexamethasone in Relapsed Refractory Multiple Myeloma

Addressing a New Challenge in Chronic Lymphocytic Leukemia: Outcomes of Therapies after Exposure to Both a Covalent Bruton's Tyrosine Kinase Inhibitor and Venetoclax

Addressing a New Challenge in Chronic Lymphocytic Leukemia: Outcomes of Therapies after Exposure to Both a Covalent Bruton's Tyrosine Kinase Inhibitor and Venetoclax

Outcomes of Chronic Lymphocytic Leukemia and Richter Transformation Following Discontinuation of Non-Covalent Bruton's Tyrosine Kinase Inhibitors

Outcomes of Chronic Lymphocytic Leukemia and Richter Transformation Following Discontinuation of Non-Covalent Bruton's Tyrosine Kinase Inhibitors

A Systematic Review and Meta-Analysis Comparing Type I and II FLT3 Inhibitors in Relapsed/ Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

Background: Acute myeloid leukemia (AML) is frequently characterized by mutations in FMS-like tyrosine kinase 3 (FLT3). FLT3 is mutated in one-third of de novo AML patients and recurrent in relapsed/refractory (R/R) AML. More frequent FLT3 internal tandem duplications (ITD) and less frequent tyrosine kinase domain (TKD) point mutations are prognostically important in AML and are associated with an inferior outcome. Although targeted therapy with FLT3 inhibitors improves prognosis in FLT3 mutated AML patients, there is a lack of evidence regarding the superiority of efficacy of various FLT3 inhibitors in clinical practice and the therapeutic pipeline. Broadly grouped as type 1 (targets ITD and TKD, e.g., midostaurin) and type 2 (targets only ITD, e.g., quizartinib) inhibitors, there is no consolidated summary of the difference in efficacy between these two classes of FLT3 inhibitors in R/R AML and high-risk myelodysplastic syndrome (HR-MDS). Hence, we conducted a systematic review and meta-analysis of various type 1 and 2 FLT3 inhibitors tested in clinical trials to compare their clinical effectiveness in treating R/R AML and HR-MDS.Methods: PubMed and EMBASE databases were searched for clinical trials published between 1/1/2000 and 5/26/2021 using a combination of keywords and subject headings related to FLT3 inhibitors and AML. Two independent reviewers screened titles/abstracts and full texts, with a third reviewer resolving conflicts. Studies were included if they were (1) full-length published journal articles that (2) reported the results of single-arm or double-arm phase I/II/III clinical trials in patients with R/R AML or HR-MDS. Outcomes of interest were composite response rate (CRc=complete response + complete response with incomplete count recovery) and overall response rate (ORR).Results: Record screening resulted in the initial inclusion of 30 studies for qualitative analysis (Fig. 1). Due to poor representation of R/R AML patients and post-transplant FLT3 inhibitor outcomes, two studies were excluded from quantitative analysis, leaving 28 studies for the final analysis. The studies had a total of 1927 R/R AML and HR-MDS patients with a median age of 61.5 years (range, 13-91) and a median of three (range, 0-10) prior lines of treatment. Giltertinib (n=3 studies) was the most frequently studied type 1 inhibitor, and quizartinib (n=6) and sorafenib (n=5) were the most frequently studied type 2 inhibitors. Heterogeneity testing using Cochran's Q test and I 2 values showed the presence of heterogeneity for both CRc (p<0.01 and I 2=87% for both type 1 and 2) and ORR (p<0.01 for both type 1 and 2, I 2=88% and 92% for type 1 and type 2, respectively) and. Hence, random-effects models were used. Asymmetry tests performed using Egger's linear regression test suggested publication bias only for type 2 (p=0.005) for ORR and type 1 and 2 for CRc (p=0.017 and 0.002, respectively). Thus, the trim-and-fill method was used to adjust for publication bias for type 2 for ORR and type 1 and 2 for CRc. Pooled ORR was 37% (95% CI, 25-51%) for type 1 and 58% (95% CI, 43-71%) for type 2. The highest ORR was for gilteritinib (68%; 95% CI, 61-73%) among type 1 and sorafenib (99%; 95% CI, 81-100%), linifanib (99%; 95% CI, 89-100%), and tandutinib (100%; 95% CI, 93-100%) for type 2 (Fig. 2). Pooled CRc was 35% (95% CI, 21-52%) for type 1 and 38% (95% CI, 27-50%) for type 2. The highest CRc was for midostaurin (98%; 95% CI, 79-100%) among type 1 and sorafenib (97%; 95% CI, 68-100%), tandutinib (98%; 95% CI, 72-100%), and semaxinib (98%; 78-100%) among type 3 (Fig. 3).Conclusion: Both type 1 and 2 inhibitors are effective as monotherapy in R/R AML and HR-MDS patients. Though not statistically significant, better ORR for type 2 than for type 1 inhibitors in the R/R setting provides a background to explore the biological heterogeneity of response and preferential sensitivity to ITD-targeted therapy alone rather than the dual inhibitor. More prospective randomized study designs comparing type 1 and 2 inhibitors in the R/R and de novo setting are needed. [Display omitted] DisclosuresMaciejewski: Bristol Myers Squibb/Celgene: Consultancy; Regeneron: Consultancy; Alexion: Consultancy; Novartis: Consultancy. Balasubramanian: Servier Pharmaceuticals: Research Funding.

Efficacy and Safety of Eltrombopag with or without Immunosuppressant in Patients with Relapsed/Refractory Acquired Aplastic Anemia: A Real-World Experience

Background: Eltrombopag (EPAG) with or without immunosuppressant (IST) has been applied in acquired aplastic anemia (AA), yet data of EPAG+IST in relapsed/refractory AA was limited, and no study has compared efficacy and safety between EPAG+IST and EPAG monotherapy in relapsed/refractory AA patients.Aims: To evaluate and compare the efficacy and safety between EPAG+IST and EPAG monotherapy in relapsed/refractory AA patients in a real-world setting.Methods: Data from patients diagnosed as acquired AA in our center were retrospectively collected. All the enrolled patients were refractory/relapsed to the standard IST for at least 6 months before EPAG. All patients had been treated with EPAG, which was started at 25 mg/day and increased every 2 weeks to a maximum of 150 mg/day until a best response was achieved. Meanwhile, some patients were treated with cyclosporin A (CsA) or tacrolimus (FK506) at the same time. EPAG had to be prescribed for at least 6 months before evaluation. Complete response (CR), overall response (OR) and relapse rate, as well as adverse events and factors which could affect efficacy were analyzed.Results: Totally 99 patients (83 non-severe AA (NSAA) and 16 SAA) were included in the study. The median age at EPAG initiation was 46 (13-88) years old, the median time of EPAG treatment was 11 (6-41) months and the median time of follow-up was 18 (6-41) months. 72 patients were treated with EPAG+IST, including 41 (56.9%) treated with EPAG+FK506 and 31 (43.1%) treated with EPAG+CsA. 27 patients were treated with EPAG alone. No significant difference was found between EPAG+IST group and EPAG group in patient baseline characteristics like age, male proportion, NSAA proportion, presence of PNH clone, proportion of previous ATG+CsA / CsA treatment, previous IST duration and dosage. With compatible follow-up time, EPAG exposure duration and dosage, there was no significant difference in OR/CR rate at 3 rd/6 th/12 th month between patients who was treated with EPAG+FK506 and EPAG+CsA. Under similar compatible baseline conditions, the OR rate was 33.3% vs 22.2% (P=0.284) at 3 rd month, 61.1% vs 37.0% (P=0.032) at 6 th month, and 67.2% vs 42.1% (P=0.051) at 12 th month for patients treated with EPAG+IST and EPAG alone, respectively, but no significant difference was found in time to response (3 (1-12) vs 3 (1-7) months, P=0.679) or CR rate at 3 rd/6 th/12 th month (6.9%/12.5%/20.7% vs 3.7%/7.4%/5.3%, P>0.05) between the two groups. Relapse occurred at 6 th to 12 th month of EPAG treatment, and the relapse rate at 12 th month was 9.8% and 27.3% (P=0.154) for patients treated with EPAG+IST and EPAG alone, respectively. For patients treated with EPAG+IST, responders had a significantly higher baseline reticulocyte count (60.25 (11.5-230.5)×10 9/L vs 16.7 (6.6-56.6)×10 9/L, P=0.040) compared with non-responders. No predictive factors for the overall response were found for patients treated with EPAG alone. Adverse events which led to dosage regulation were gastrointestinal disorders (2.8% vs 3.7%, P=1.000), elevated creatinine (2.8% vs 0, P=0.599), elevated ALT (1.4% vs 0, P=1.000) and arthralgia (0 vs 3.7%, P=0.280) for patients with EPAG+IST and EPAG, respectively. No deaths were found in either group, while the clone evolution rate was 2.8% and 3.7% (P=1.000) in EPAG+IST and EPAG monotherapy group, respectively.Conclusion: EPAG+IST had higher OR rate than EPAG monotherapy with similar side effects for patients with relapsed/refractory acquired AA. Those with higher baseline reticulocyte count were more likely to respond to EPAG+IST.Key words: relapsed/refractory, aplastic anemia, eltrombopag, immunosuppressant, efficacy DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:In the presented study, eltrombopag was prescribed in relapsed/refractory aplastic anemia patients.

Chidamide Maintenance Therapy after Induction or Salvage Treatment in Patients with Peripheral T-Cell Lymphoma Ineligible for Autologous Stem Cell Transplantation

BackgroundPeripheral T-cell lymphoma (PTCL) is a set of rare and heterogeneous clinically aggressive mature T- and natural killer cell neoplasms, all of which are associated with poor prognosis. PTCL treatments are usually associated with a high failure rate and frequent relapses. To improve the poor clinical outcomes of PTCL, novel agents that target various pathways have been intensively studied and developed. Histone deacetylase (HDAC) inhibitors are among the most significant improvements made in recent years. Chidamide, a novel benzamide class of HDAC inhibitor, showed significant efficacy in relapsed/refractory PTCL patients in previous studies. In China, a high percentage of PTCL patients are elderly and not suitable for transplantation, and many patients cannot afford transplantation. There is an urgent medical need for maintenance therapy for PTCL patients, and chidamide single-agent maintenance therapy may benefit PTCL patients ineligible for autologous stem cell transplantation (ASCT) with its proven outstanding antitumor effects.MethodsIn this prospective, single-center, single-arm study, a total of 43 patients with PTCL, including angioimmunoblastic T-cell lymphoma (AITL) (44.2%), anaplastic large-cell lymphoma, ALK − (ALCL, ALK −) (11.6%), PTCL-not otherwise specified (PTCL-NOS) (14.0%), extranodal NK/T-cell lymphoma (NKT) (16.3%), and other PTCL subtypes (14.0%), were enrolled from January 2016 to March of 2021. All patients were ineligible for transplantation. They had a median age of 59 years (22-80). Thirty-six patients (83.7%) received chidamide maintenance after induction treatment, and 7 patients (16.3%) started chidamide maintenance treatment after salvage treatment. Endpoints included progress-free survival (PFS), overall survival (OS), and safety assessment.ResultsUntil April 2021, the median follow-up time was 10.1 months (2-64.5). The complete remission rate (CR) was 44.2% and overall response rate (ORR) was 79.1%. The median PFS was 24.3 m, and the 1-year PFS rate was 68.1%. The median OS has not yet been reached, and 1-year OS rate was 84.3%. Stratified analyses of PFS and OS showed no significant differences. Grade 3/4 adverse events were mainly hematological toxicities, including neutropenia, leukopenia, thrombocytopenia, and anemia, and they were well tolerated.When used a first-line/1.5-line treatment, i.e., for patients who had achieved CR after introduction treatment (12 cases) or who did not achieve CR but received chidamide + chemotherapy consolidation treatment (24 cases), chidamide maintenance therapy was found to maintain the effect of CR (in all 12 patients) or improve the clinical outcomes to CR/PR (partial remission) (9 out of the 24 patients). Even when used after salvage treatment, chidamide maintenance was found to achieve PR and better efficacy in 4 out the 7 patients.ConclusionsChidamide maintenance treatment achieved significantly high CR and ORR rates for PTCL patients. This therapy may improve PFS and OS with a manageable safety profile for PTCL patients. This treatment thus may benefit PTCL patients who are ineligible for or cannot afford ASCT, which is an especially severe problem in China. Further large-scale, multi-center, randomized studies are required to extensively examine the efficacy and safety of chidamide maintenance therapy in PTCL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pembrolizumab Plus Vorinostat Induces Responses in Patients with Hodgkin Lymphoma Who Are Refractory to Prior PD-1 Blockade

Pembrolizumab Plus Vorinostat Induces Responses in Patients with Hodgkin Lymphoma Who Are Refractory to Prior PD-1 Blockade

Outcomes with “Off the Shelf” Allogeneic CD19 Chimeric Antigen Receptor T Cell Therapy for Hematological Malignancies: A Systematic Review and Meta-Analysis

Background:Chimeric antigen receptor T cell (CAR-T) therapy is an adoptive T cell immunotherapy that employs the genetically modified T cell to attack the cancer cell. It is widely studied across various hematological and solid organ malignancies. Several autologous CD19 CAR-T cell therapy constructs are now approved for various B cell lymphomas, including aggressive B cell lymphomas, indolent follicular lymphoma and mantle cell lymphoma, and acute lymphoblastic leukemia (ALL). Autologous CD19 CAR-T cell therapy has unprecedented success in relapsed and refractory disease. Long time to manufacture (2-5 weeks) and manufacture failure are challenges associated with risk of interim death and deterioration of CAR-T candidates with rapidly progressive disease. T cell fitness of the autologous product in heavily pretreated patients is also potentially compromised. To overcome these shortcomings, universal “off the shelf” allogeneic CAR-T cell therapy constructs are being developed and studied. Donor sources include healthy donors and cord or induced pluripotent stem cells (iPSCs). These CAR-T constructs have additional gene modifications to mitigate the risk of rejection and graft versus host disease (GVHD). We performed a systematic review and meta-analysis to assess the safety and efficacy of allogeneic CD19 CAR-T cell therapy.Methods:Four databases (Web of Science/MEDLINE/PubMed, Embase, and Cochrane Registry of Controlled Trials) were searched for this systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines using MeSH terms and keywords for “Receptors, Chimeric antigen” OR “Artificial-T-cell receptor” OR “immunotherapy, adoptive” OR “CD-19”. Our search produced 3506 articles and after removing duplicates, 2243 records were screened. After excluding reviews and irrelevant articles, we included 8 prospective trials of allogeneic CD-19 CAR-T cell therapy enrolling two or more than two patients from Jan 2013 to Nov 2020. We also searched ASH 2020 abstracts to include any additional trials. The methodological quality of the included studies was evaluated using NIH quality assessment tool. Inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2).Results:A total of 68 patients from 8 studies were evaluated. Median age was 22.5 (4.8-64) years. (Table 1) The median follow-up time was 10 (2-18) months with median number of prior therapies of 3.2 (2-11) as reported by 5 studies. Underlying diagnosis was acute lymphocytic lymphoma (n=49, 72%), chronic lymphocytic leukemia (n=6, 9%), and non-Hodgkin lymphoma (n=13, 19%). The pooled overall response rate (ORR) was 77% (95% CI 0.63-0.89, I 2 =22%, n=68) with a complete response (CR) of 75% (95% CI 0.57-0.90, I 2 =48%, n=65). The pooled incidence of cytokine release syndrome grade I/II and grade III/IV was 53% (95% CI 0.16-0.89, I 2 =89%, n=65) and 10% (95% CI 0.01-0.25, I 2 =50%, n=65) respectively. Neurotoxicity grade I/II was 12% (95%CI 0.01-0.30, I 2 =47%, p=0.09, n=47) and GVHD grade I/II was 8% (95%CI 0.01-0.19, I 2 =0%, p=0.57 n=53). None of the clinical trials reported the duration of response.Conclusion:“Off the shelf” universal CAR-T therapy is early in development. Our available data suggest that allogeneic CD19 CAR-T constructs offer high ORR and CR rates with acceptable safety profiles. GVHD was mainly low grade (grade I-II). Given these findings, allogeneic CAR-T cell therapy is an attractive option to improve timely access compared to available autologous therapy. Extensive preclinical research to develop novel constructs and several phase I/II clinical trials are ongoing to shape the future of “off the shelf” CAR-T cell therapy. [Display omitted] DisclosuresHoffmann: Pharmcyclics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Pluristem Therapeutics: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Astelllas Pharma: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Allovir: Consultancy, Honoraria, Research Funding.

Evaluation of the Efficacy of Cyclosporin A Combined with Recombined Human Erythropoietin in the Treatment of Patients with Chronic Aplastic Anemia

Objective To compare the efficacy and safety of cyclosporin A(CsA)and CsA combined with recombined human erythropoietin(rhEPO)in the treatment of patients with chronic aplastic anemia(CAA).Methods Data of 79 patients with CAA treated at Department of Hematology,PUMC Hospital between January 2016 and June 2018 were collected for retrospective analysis.Forty-five patients were treated with CsA+rhEPO,and the other 34 patients with CsA alone.All the enrolled patients were treated for at least 1.5-2.0 years and followed for at least 1.0 year.The efficacy,side effects,long-term outcomes were compared between the two groups,and factors that may influence the efficacy were analyzed.Results The patients treated with CsA+rhEPO included 14 males and 31 females,with a median age of 43(19,73)years old.The median treatment duration of CsA and rhEPO was 26(12,38)and 4(3,6)months,respectively,and the median followed-up time was 24(12,42)months.The patients treated with CsA alone included 16 males and 18 females,with a median age of 36(16,85)years old.The median CsA treatment duration was 24(12,40)months and the median follow-up time was 25(12,40)months.There was no statistical difference in baseline characteristics between the two groups(all P>0.05).After 6 months of treatment,CsA+rhEPO group had higher overall response(OR)rate(55.6% vs. 31.3%;χ 2=4.456,P=0.040)and partial response(PR)rate(53.3% vs. 25.0%;χ2=6.181,P=0.019)than CsA group,and the complete response(CR)rate showed no statistical difference between the two groups(2.2% vs. 6.3%;χ2=0.810,P=0.567).The CR,PR,and OR rates showed no statistical difference between the two groups after 3 and 12 months of treatment and at the end of follow-up(all P>0.05).Similarly,the hemoglobin level at the sixth month of treatment with CsA+rhEPO was higher than that with CsA alone [(102.6±24.0)g/L vs.(90.3±29.1)g/L;t=2.017,P=0.047].However,it showed no significant difference between the two groups at other time points(all P>0.05).The side effects,including an increase in serum creatinine,slight increase in bilirubin,increase in aminotransferase,mild to moderate gingival hyperplasia,gastrointestinal reaction,and muscular fibrillation,had no significant differences between the two groups(all P>0.05),except that 11.1%(5/45)patients in the CsA+rhEPO group reported soreness at the injection site.The two groups showed similar rates of clonal revolution during the follow-up period and no death.No clinical factor was found for prediction of the efficacy of CsA+rhEPO. Conclusion CsA+rhEPO has higher OR rate and hemoglobin level than CsA alone at the sixth month of treatment,and it has similar side effects compared with CsA alone.

Tre-O1-02 - Real world data shows that chlormethine gel is efficient and safe in mycosis fungoides skin lesions

<h3>Background:</h3> Chlormethine gel is a skin-directed therapy used for patients with mycosis fungoides (MF) that has shown promising results in a randomized clinical trial. Currently, data on chlormethine gel use in real-world settings is limited. <h3>Objectives:</h3> To assess safety and efficacy of chlormethine gel treatment in patients treated during daily clinical practice, and investigate associations between response and disease stage, lesion type, mono- or combination therapy, and occurrence of dermatitis. <h3>Methods:</h3> A retrospective chart review of patients using chlormethine gel from 3 sites in Greece was performed. Efficacy was assessed through modified Severity-Weighted Assessment Tool (mSWAT) scores. Safety assessments included analysis of the occurrence and severity of dermatitis. The Skindex-29 questionnaire was used to evaluate quality of life. <h3>Results:</h3> A total of 58 patients were included. The overall response rate (ORR) increased from 37.9% at month 1 to 80.8% at month 9. For 64.2% of patients, response was maintained for at least 4 months (ORR4). At month 3, a higher ORR was seen for patients with patches (69.7%) than patients with plaques/tumors (both 15.2%). A higher ORR4 was observed for patients with early-stage vs late-stage disease (71.4% vs 36.4%) and patients on mono- vs combination therapy (75% vs 47.6%). Dermatitis was observed in the majority of patients (72.4%), but the presence or severity of dermatitis was not directly correlated with treatment response. Both mSWAT and Skindex-29 scores decreased significantly during treatment, and changes in these scores from baseline to month 6 showed a positive correlation (r=0.55, p=0.026). <h3>Conclusions:</h3> Chlormethine gel treatment was effective for patients with all stages of MF in clinical practice, although patients with patch-stage or early-stage disease may have higher response rates or more durable responses compared with patients with more-advanced disease. Response rates increased over time, indicating that continued treatment with the gel is important. Dermatitis may be managed by reducing the treatment frequency, and the occurrence of dermatitis did not affect the response to CL gel treatment.

Histone Deacetylase as a Valuable Predictive Biomarker and Therapeutic Target in Immunotherapy for Non-Small Cell Lung Cancer.

PurposeHistone deacetylase inhibitors (HDACis) are epigenetic regulators and used clinically for hematopoietic malignancies. Recently, HDACis have received attention as a factor that modulates the immune system. In this study, the role of histone deacetylase (HDAC) expression as a predictive marker in lung cancer patients who were treated with immune checkpoint inhibitors (ICIs) and the role of HDACi and ICI combination treatment in the mouse tumor model were analyzed.Materials and MethodsThe overall response rate (ORR) and progression-free survival (PFS) were analyzed by the expression of HDAC. In vitro assay, the mRNA and protein expression levels of cytokines and programmed death-ligand 1 (PD-L1) were analyzed after HDACi treatment. In vivo assay, TC-1 tumor-bearing mice were treated with HDACi and mouse programmed cell death 1 (PD-1) inhibitor.ResultsThe HDAC6 low expression group showed high ORR and prolonged PFS. When the selective HDAC6 inhibitor was administered to the A549 cell line, the levels of interleukin-1β and interleukin-6 decreased and the expression of PD-L1 was reduced. Mice that received both the mouse PD-1 inhibitor and pan-HDACi had a smaller tumor size than that of the mice from the control group. Moreover, mice treated with the mouse PD-1 inhibitor and pan-HDACi generated greater numbers of E7-specific CD8+ T cells.ConclusionHDAC6 expression can predict the prognosis of non–small cell lung cancer patients who were treated with ICIs. Furthermore, co-treatment with HDACi and PD-1 inhibitor was shown to decrease the tumor growth rate and create a favorable tumor microenvironment for cytotoxic T lymphocytes in the TC-1 mouse model.

Real-world data from a Molecular Tumor Board: improved outcomes in gynecologic and breast cancer patients with precision medicine

Objectives: Next-generation sequencing (NGS) is being increasingly utilized in gynecologic and breast cancers. Multidisciplinary Molecular Tumor Board (MTB) may guide an N-of-One approach in order to maximize matched treatment; however, outcome data are limited. We evaluate the effect of the degree of matching patients to treatment and concordance with MTB recommendations on oncologic outcomes, including overall response rate (ORR), clinical benefit rate (CBR) (stable disease ≥6 months/partial or complete remission), progression-free survival (PFS), and overall survival (OS). Methods: 164 consecutive gynecologic and breast cancer patients presented at MTB from December 2012-September 2018 were assessed for clinicopathologic data, NGS results, MTB recommendations, therapy received, and oncologic outcomes. Matching score (MS), defined as percentage of alterations targeted by treatment out of total number of pathogenic alterations, and concordance with MTB recommendations were analyzed in context of oncologic outcomes. Disease site, age, and number of prior lines of therapy were considered as covariates in univariate analysis and included in multivariate analysis if p<0.2. Results: 113 women were evaluable for treatment after MTB; 54% received matched therapy. Patients with MS > 40% had higher ORR (30.8% vs. 7.1%; p=0.001) and CBR (73.1% vs. 31.2%; p<0.001) (Figure 1), PFS (HR 0.51, 95% CI 0.31, 0.85; p=0.002), and a trend toward improved OS (HR=0.64, 95% CI 0.34, 1.25; p=0.082) in univariate analysis. Higher MS was associated with improved ORR (HR 5.9, 95% CI 1.8, 19.0; p=0.003), CBR (HR 4.8, 95% CI 1.7, 13.4; p=0.003), and PFS (HR 0.5, 95% CI 0.3, 0.8; p=0.006) in multivariate analyses. Higher concordance with MTB recommendations was significantly associated with improved median PFS (9.0 months for complete concordance; 6.0 months for partial concordance; 4.0 months for no concordance; p=0.004) and OS (17.1 months complete concordance, 17.8 months partial concordance, 10.8 months no concordance; p=0.046). Patients who received completely MTB-concordant treatment had higher MS (p<0.001). In multivariate analysis comparing all vs none for concordance with MTB recommendations, PFS (HR 9.5; 95% CI 2.6, 35.0; p=0.001) and OS (HR 8.8, 95% CI 2.4, 33.2; p=0.001) remained significant. Conclusions: Concordance with MTB recommendations resulted in higher degrees of matched therapy and was associated with improved oncologic outcomes in gynecologic and breast cancer patients. Next-generation sequencing (NGS) is being increasingly utilized in gynecologic and breast cancers. Multidisciplinary Molecular Tumor Board (MTB) may guide an N-of-One approach in order to maximize matched treatment; however, outcome data are limited. We evaluate the effect of the degree of matching patients to treatment and concordance with MTB recommendations on oncologic outcomes, including overall response rate (ORR), clinical benefit rate (CBR) (stable disease ≥6 months/partial or complete remission), progression-free survival (PFS), and overall survival (OS). 164 consecutive gynecologic and breast cancer patients presented at MTB from December 2012-September 2018 were assessed for clinicopathologic data, NGS results, MTB recommendations, therapy received, and oncologic outcomes. Matching score (MS), defined as percentage of alterations targeted by treatment out of total number of pathogenic alterations, and concordance with MTB recommendations were analyzed in context of oncologic outcomes. Disease site, age, and number of prior lines of therapy were considered as covariates in univariate analysis and included in multivariate analysis if p<0.2. 113 women were evaluable for treatment after MTB; 54% received matched therapy. Patients with MS > 40% had higher ORR (30.8% vs. 7.1%; p=0.001) and CBR (73.1% vs. 31.2%; p<0.001) (Figure 1), PFS (HR 0.51, 95% CI 0.31, 0.85; p=0.002), and a trend toward improved OS (HR=0.64, 95% CI 0.34, 1.25; p=0.082) in univariate analysis. Higher MS was associated with improved ORR (HR 5.9, 95% CI 1.8, 19.0; p=0.003), CBR (HR 4.8, 95% CI 1.7, 13.4; p=0.003), and PFS (HR 0.5, 95% CI 0.3, 0.8; p=0.006) in multivariate analyses. Higher concordance with MTB recommendations was significantly associated with improved median PFS (9.0 months for complete concordance; 6.0 months for partial concordance; 4.0 months for no concordance; p=0.004) and OS (17.1 months complete concordance, 17.8 months partial concordance, 10.8 months no concordance; p=0.046). Patients who received completely MTB-concordant treatment had higher MS (p<0.001). In multivariate analysis comparing all vs none for concordance with MTB recommendations, PFS (HR 9.5; 95% CI 2.6, 35.0; p=0.001) and OS (HR 8.8, 95% CI 2.4, 33.2; p=0.001) remained significant. Concordance with MTB recommendations resulted in higher degrees of matched therapy and was associated with improved oncologic outcomes in gynecologic and breast cancer patients.

The efficacy and safety profile of ixazomib/lenalidomide/dexamethasone in relapsed/refractory multiple myeloma: a multicenter real-world study in China

目的评估伊沙佐米、来那度胺、地塞米松（IRd）方案治疗复发/难治多发性骨髓瘤（MM）的疗效及安全性。方法纳入2018年7月至2020年5月于国内14个中心接受至少1个周期IRd方案治疗的复发/难治MM患者。除7例起始剂量作调整的患者以外，其余患者伊沙佐米起始剂量为4 mg。来那度胺剂量根据患者肌酐清除率进行调整。每周期进行疗效及安全性评估。结果共纳入74例患者，中位年龄65岁，11例（14.9％）患者曾接受>三线治疗。总体反应率（ORR）为54.1％（40/74），其中7例（9.5％）达严格意义的完全缓解或完全缓解，14例（18.9％）达非常好的部分缓解，19例（25.7％）达部分缓解，中位无进展生存时间为9.9月，中位总生存时间为20个月，中位获得反应时间为1个月。总体疗效与生存结果与TOURMALINE-MM1中国延展性研究（TOURMALINE-MM1 CCS）相近。硼替佐米难治、来那度胺难治、两药均难治患者的ORR分别为52.0％（13/25）、57.1％（4/7）和33.3％（6/18）。3～4级不良事件（AE）发生率为36.5％（27/74）。主要血液学不良反应为贫血、血小板减少、淋巴细胞减少及中性粒细胞减少。主要非血液学不良反应为乏力、消化道症状及感染。2例患者出现3级周围神经病变。与不符合TOURMALINE-MM1 CCS试验入组标准的患者相比，符合入组标准的患者ORR更高［77.8％（14/18）对46.4％（26/56），P＝0.020］，两组3～4级AE发生率的差异无统计学意义［33.3％（6/18）对37.5％（21/56），P＝0.749］。结论IRd方案治疗复发/难治MM具有较好的疗效及安全性。