Personalized neoantigen vaccine enhances the therapeutic efficacy of bevacizumab and anti-PD-1 antibody in advanced non-small cell lung cancer.

Clinically, a considerable number of non-small cell lung cancer (NSCLC) patients are unable to receive or resist chemotherapy, and the efficacy of non-chemotherapy treatment strategies based on anti-angiogenic agents combined with immune checkpoint blockade is still unsatisfactory. Neoantigen vaccine, based on personalized tumor DNA mutations, could elicit tumor specific T cell infiltration into the tumor site, exerting potent anti-tumor efficacy. Here, we evaluated the feasibility and safety of a new antitumor strategy by adding neoantigen vaccine to the regimen of bevacizumab and anti-PD-1 antibody. Firstly, 7 novel immunogenic neoantigen peptides were identified and developed for neoantigen vaccine (LLCvac), which can elicit strong antitumor immune response in vivo. Then, in orthotopic lung cancer model, LLCvac further combining with bevacizumab and anti-PD-1 antibody exerted a stronger antitumor effect, exhibiting significant decrease of tumor volume without obvious toxicity. Furthermore, tumor immune microenvironment assessment also showed that the proportion of neoantigen-specific T cells in blood could be induced dramatically by the combined therapy. And a large amount of neoantigen-specific Ki67-positive CD8+ T cells were found in tumor tissues, which infiltrated tumor tissues effectively to kill tumor cells expressing identified neoantigens. Overall, these results suggested that this combined therapy could safely induce robust antitumor efficacy, serving as an effective chemotherapy-free strategy for NSCLC treatment.

Incidence, risk factors, and outcomes of second neoplasms in patients with acute promyelocytic leukemia: the PETHEMA-PALG experience.

The most important challenges in acute promyelocytic leukemia (APL) is preventing early death and reducing long-term events, such as second neoplasms (s-NPLs). We performed a retrospective analysis of 2670 unselected APL patients, treated with PETHEMA "chemotherapy based" and "chemotherapy free" protocols. Only de novo APL patients who achieved complete remission (CR) and completed the three consolidation cycles were enrolled into the analysis. Out of 2670 APL patients, there were 118 (4.4%) who developed s-NPLs with the median latency period (between first CR and diagnosis of s-NPL) of 48.0 months (range 2.8-231.1): 43.3 (range: 2.8-113.9) for s-MDS/AML and 61.7 (range: 7.1-231.1) for solid tumour. The 5-year CI of all s-NPLs was of 4.43% and 10 years of 7.92%. Among s-NPLs, there were 58 cases of s-MDS/AML, 3 cases of other hematological neoplasms, 57 solid tumours and 1 non-identified neoplasm. The most frequent solid tumour was colorectal, lung and breast cancer. Overall, the 2-year OS from diagnosis of s-NPLs was 40.6%, with a median OS of 11.1 months. Multivariate analysis identified age of 35 years (hazard ratio = 0.2584; p < 0.0001) as an independent prognostic factor for s-NPLs. There were no significant differences in CI of s-NPLs at 5 years between chemotherapy-based vs chemotherapy-free regimens (hazard ratio = 1.09; p = 0.932). Larger series with longer follow-up are required to confirm the potential impact of ATO+ATRA regimens to reduce the incidence of s-NPLs after front-line therapy for APL.

Mobilization-based engraftment of haematopoietic stem cells: a new perspective for chemotherapy-free gene therapy and transplantation.

INTRODUCTION: In haematopoietic stem cell transplantation (HSCT), haematopoietic stem cells (HSCs) from a healthy donor replace the patient's ones. Ex vivo HSC gene therapy (HSC-GT) is a form of HSCT in which HSCs, usually from an autologous source, are genetically modified before infusion, to generate a progeny of gene-modified cells. In HSCT and HSC-GT, chemotherapy is administered before infusion to free space in the bone marrow (BM) niche, which is required for the engraftment of infused cells. Here, we review alternative chemotherapy-free approaches to niche voidance that could replace conventional regimens and alleviate the morbidity of the procedure. SOURCES OF DATA: Literature was reviewed from PubMed-listed peer-reviewed articles. No new data are presented in this article. AREAS OF AGREEMENT: Chemotherapy exerts short and long-term toxicity to haematopoietic and non-haematopoietic organs. Whenever chemotherapy is solely used to allow engraftment of donor HSCs, rather than eliminating malignant cells, as in the case of HSC-GT for inborn genetic diseases, non-genotoxic approaches sparing off-target tissues are highly desirable. AREAS OF CONTROVERSY: In principle, HSCs can be temporarily moved from the BM niches using mobilizing drugs or selectively cleared with targeted antibodies or immunotoxins to make space for the infused cells. However, translation of these principles into clinically relevant settings is only at the beginning, and whether therapeutically meaningful levels of chimerism can be safely established with these approaches remains to be determined. GROWING POINTS: In pre-clinical models, mobilization of HSCs from the niche can be tailored to accommodate the exchange and engraftment of infused cells. Infused cells can be further endowed with a transient engraftment advantage. AREAS TIMELY FOR DEVELOPING RESEARCH: Inter-individual efficiency and kinetics of HSC mobilization need to be carefully assessed. Investigations in large animal models of emerging non-genotoxic approaches will further strengthen the rationale and encourage application to the treatment of selected diseases.

Pharmacoeconomic issues in stem cell mobilization.

BACKGROUND: recently, stem cell mobilization has made dramatic progress, that ended up in an increasing number of aphereses at target for autologous peripheral stem cell transplantation (ASCT). The aim of this research is investigating the cost-effectiveness of stem cell mobilization. METHODS: a narrative review of the literature was carried out, searching for primary contributions written in English and published during 2000-2023 on cost-effectiveness analysis (CEA) of stem cell mobilization in patients entitled to ASCT. The PubMed database was searched with the following sets of keywords: cost-effectiveness AND apheresis AND myeloma (PubMed_1); cost-effectiveness AND stem cell mobilization (PubMed_2). Articles included in the analysis were assessed via two different checklists. RESULTS: sixty-six entries were retrieved. Five out of 66 (PubMed_1: 4 out 17; PubMed_2: 1 out of 49), 4 CEAs and 1 cost-utility analysis (CUA) fit the research goal. Four out of 5 contributions proved to be in line with most of the items included in the two assessment grids. However, the most relevant missing features in some of the included contributions were: study perspective, healthcare resources valuation, and sensitivity analyses. DISCUSSION: most of the articles included in this research show that chemotherapy-free stem cell mobilization is cost-effective according to different standpoints. Future health economic research on this topic should establish local threshold values for incremental apheresis at target and explore the heterogeneity of CEA (and CUA) to determine oncohaematological diseases and patient categories for which chemotherapy-free stem cell mobilization is cost-effective in different healthcare systems, given local budget constraints.

Efficacy and safety of combined immunotherapy and antiangiogenic therapy for advanced non-small cell lung cancer: a real-world observation study.

PURPOSE: This study was performed to investigate the efficacy and safety of combined immunotherapy and antiangiogenic therapy for advanced non-small cell lung cancer (NSCLC) in the real world. METHODS: Data on clinicopathological features, efficacy and adverse events (AEs) were collected retrospectively in advanced NSCLC patients who received immunotherapy combined with antiangiogenic therapy. RESULTS: A total of 85 advanced NSCLC patients were enrolled. The patients had a median progression-free survival (PFS) of 7.9 months and a median overall survival (OS) of 18.60 months. The objective response rate and disease control rate were 32.9% and 83.5%, respectively. Subgroup analysis revealed that NSCLC patients with stage IV (p = 0.042), brain metastasis (p = 0.016) and bone metastasis (p = 0.016) had shorter PFS. NSCLC patients with brain metastasis (p = 0.025), liver metastasis (p = 0.012), bone metastasis (p = 0.014) and EGFR mutations (p = 0.033) had shorter OS. Multivariate analysis revealed that brain metastasis (HR = 1.798, 95% CI: 1.038, 3.112, p = 0.036) and bone metastasis (HR = 1.824, 95% CI: 1.077, 3.090, p = 0.025) were independent predictive factors of PFS, and bone metastasis (HR = 2.00, 95% CI: 1.124, 3.558, p = 0.018) was an independent predictive factor of OS. In addition, patients receiving immunotherapy combined with antiangiogenic therapy in second-line therapy had longer OS than those receiving immunotherapy in third- or later-line therapy (p = 0.039). Patients with EGFR mutations who received combination therapy had worse OS than those with KRAS mutations (p = 0.026). Furthermore, PD-L1 expression was associated with treatment responses in advanced NSCLC (χ2 = 22.123, p = 0.000). AEs of different grades occurred in 92.9% (79/85) of NSCLC patients, most of which were mild grade 1/2 AEs. No grade 5 fatal AEs occurred. CONCLUSION: Immunotherapy combined with antiangiogenic therapy was an option for advanced NSCLC patients with good safety and tolerability. Brain metastases and bone metastases were potentially independent negative predictors of PFS. Bone metastases were a potential independent negative predictor of OS. PD-L1 expression was a potential predictor of response for immunotherapy combined with antiangiogenic therapy.

How Have Targeted Agents Changed the Treatment Landscape for Elderly Patients with CLL?

PURPOSE OF REVIEW: Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy in elderly patients. At the time of diagnosis, most patients have comorbid medical conditions. Although patients have other competing medical issues, the majority of patients will die from CLL or CLL-related complications. This review will discuss treatment in elderly patients with CLL. RECENT FINDINGS: Recent work has focused on understanding the role comorbid medical conditions play in the management of CLL in elderly patients, including the use of geriatric assessment, Charlson comorbidity index, cumulative illness rating scale, and most recently, the CLL-comorbidity index. The treatment landscape for CLL has shifted from chemoimmunotherapy to the use of targeted agents. Several clinical trials in elderly patients have demonstrated improvement in progression-free survival (PFS) with ibrutinib + / - obinutuzumab, acalabrutinib + / - obinutuzumab, zanubrutinib, venetoclax-obinutuzumab, idelalisib, and duvelisib. The adverse event profile and potential for drug-drug interactions in the treatment of CLL in elderly patients have not been described, and further studies are needed to determine optimal treatment. Treatment of elderly patients with CLL should be made on a case-by-case basis based on a patient's fitness, comorbid medical conditions, and concomitant medications. The use of targeted agents has improved outcomes in this patient population, but further studies are needed to determine the best practice.

Significance of chemotherapy-free interval and tumor regression grade in patients with recurrent esophageal squamous cell carcinoma receiving chemotherapy with fluorouracil and platinum after esophagectomy following preoperative chemotherapy.

BACKGROUND: In Japan, standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC) includes preoperative chemotherapy with fluorouracil plus cisplatin followed by esophagectomy. However, its efficacy is unclear in patients with recurrent disease with < 6 months of chemotherapy-free interval (CFI) after preoperative chemotherapy followed by esophagectomy and in those with ≥ 6 months of CFI and poor pathological response to prior preoperative chemotherapy. METHOD: We retrospectively evaluated the efficacy of fluorouracil plus platinum in patients with recurrent ESCC who received preoperative chemotherapy followed by curative esophagectomy. RESULTS: Among 105 patients with recurrent ESCC after preoperative chemotherapy followed by esophagectomy, a total of 55 patients received fluorouracil plus platinum for recurrent disease. Patients with a CFI < 6 months (n = 20) had significantly shorter overall survival (OS) (median, 7.1 vs 14.5 months, P = 0.008) compared with those with a CFI ≥ 6 months (n = 35). Multivariate analysis showed that OS was worse in patients with a CFI < 6 months or a tumor regression grade (TRG) ≤ 1a. Furthermore, in patients with a CFI ≥ 6 months, TRG ≤ 1a was associated with significantly shorter OS (11.1 months vs. not reached, P = 0.001). CONCLUSION: Fluorouracil plus platinum was ineffective for recurrent ESCC in patients with a CFI < 6 months and in those with a CFI ≥ 6 months and a TRG ≤ 1a. Alternate regimens including nivolumab or pembrolizumab might be considered for the treatment for recurrence in these patients.

M7-FLIPI is not prognostic in follicular lymphoma patients with first-line rituximab chemo-free therapy.

The clinical course of follicular lymphoma (FL) is highly variable. Recently the m7-FL international prognostic index (FLIPI) integrating performance status, FLIPI score and the mutational status of seven genes, was shown to stratify patients into "low-risk" and "high-risk" with respect to 5-year failure-free survival after first-line immunochemotherapy. Our aim was to evaluate the model after rituximab without chemotherapy. The Nordic Lymphoma Group performed two randomized clinical trials on indolent lymphoma patients receiving single rituximab and rituximab with interferon-α2a. In total, 95 FL patients had sufficient fresh-frozen diagnostic material for sequencing. A targeted panel for the genes EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11 was utilized for m7-FLIPI score calculation. With a median follow-up of 10·6 years, 76% of patients were alive. No difference in time to treatment failure (TTF), defined as the interval between start of trial therapy and initiation of new therapy or death, nor overall survival (OS) was found between the m7-FLIPI risk groups (log-rank P = 0·94 and 0·99, respectively). EZH2 mutations were associated with longer TTF (log-rank P = 0·04) and in EP300 mutations were associated with shorter TTF (log-rank P = 0·01). We conclude that the prognostic value of the m7-FLIPI clinicogenetic model seems dependent on therapeutic regimen.

Novel Therapies for Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

The most common type of non-Hodgkin lymphoma in adults is diffuse large B-cell (DLBCL). There is a historical unmet need for more effective therapies in the 2nd and 3rd line setting. Emerging immunochemotherapies have shown activity in small studies of heavily pre-treated patients with prolonged remissions achieved in some patients. Anti-CD19 CAR (chimeric antigen receptor) T cells are potentially curative in the 3rd line and beyond setting and are under investigation in earlier lines of therapy. Antibody-drug conjugates (ADC's) such as polatuzumab vedotin targeting the pan-B-cell marker CD79b has proven effectiveness in multiply-relapsed DLBCL patients. Tafasitamab (MOR208) is an anti-CD19 monoclonal antibody producing prolonged remissions when combined with Lenalidomide (LEN) in patients who were not candidates for salvage chemotherapy or autologous stem cell transplant. Selinexor, an oral, small-molecule selective inhibitor of XPO1-mediated nuclear export (SINE), demonstrated prolonged activity against heavily-pretreated DLBCL without cumulative toxicity and is being investigated as part of an oral, chemotherapy-free regimen for relapsed aggressive lymphoma. This article reviews current strategies and novel therapies for relapsed/refractory DLBCL.

Lurbinectedin in patients with small cell lung cancer with chemotherapy-free interval ≥30 days and without central nervous metastases.

OBJECTIVES: This report focuses on lurbinectedin activity and safety in a subgroup of small cell lung cancer (SCLC) patients from a Basket phase 2 study (Trigo et al. Lancet Oncology 2020;21:645-654) with chemotherapy-free interval (CTFI) ≥ 30 days. This pre-planned analysis was requested for obtaining regulatory approval of lurbinectedin in Switzerland. MATERIALS AND METHODS: Patients with extensive-stage SCLC, no central nervous system (CNS) metastases, and disease progression after platinum-containing therapy were included. Topotecan data from a contemporary, randomized, controlled phase 3 study (ATLANTIS) were used as indirect external control in a matched patient population (n = 98 patients). RESULTS: Lurbinectedin showed a statistically significant higher overall response rate (ORR) by investigator assessment (IA) compared to topotecan subgroup (41.0 % vs. 25.5 %; p = 0.0382); higher ORR by Independent Review Committee (IRC) (33.7 % vs. 25.5 %); longer median duration of response (IA: 5.3 vs. 3.9 months; IRC: 5.1 vs. 4.3 months), and longer median overall survival (10.2 vs. 7.6 months). Grade ≥ 3 hematological abnormalities were remarkably lower with lurbinectedin: anemia 12.0 % vs. 54.1 %; leukopenia 30.1 % vs. 68.4 %; neutropenia 47.0 % vs. 75.5 %, and thrombocytopenia 6.0 % vs. 52.0 %. Febrile neutropenia was observed at a higher incidence with topotecan (6.1 % vs. 2.4 % with lurbinectedin) despite that the use of growth-colony stimulating factors was mandatory with topotecan. CONCLUSION: With the limitations of an indirect comparison, however using recent and comparable SCLC datasets, this post hoc analysis shows that SCLC patients with CTFI ≥ 30 days and no CNS metastases have a positive benefit/risk ratio with lurbinectedin, superior to that observed with topotecan.

Novel treatment for mantle cell lymphoma - impact of BTK inhibitors and beyond.

Mantle cell lymphoma (MCL) primarily affects older adults, accounting for 3-10% of all non-Hodgkin lymphoma (NHL) in western countries. The disease course of MCL is heterogenous; driven by clinical, cytogenetics, and molecular features that shape differences in outcomes, including proliferation index, MIPI scores, and mutational profile such as TP53 aberration. The advent of novel agents has fundamentally evolved the treatment landscape for MCL with treatment strategies that can now be more effectively tailored based on both patient- and disease-specific factors. In this review, we discuss the major classes of novel agents used for the treatment of MCL, focusing on efficacy and notable toxicities of BTK inhibitors. We further examine effective novel combination regimens and, lastly, discuss future directions for the evolution of targeted approaches for the treatment of MCL.

SOHO State of the Art Updates and Next Questions: Update on the Approach to Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

The outcome of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) has improved significantly following the introduction of the BCR::ABL1 tyrosine kinase inhibitors (TKIs). The addition of newer-generation and more potent TKIs resulted in higher rates of molecular responses and better survival. Achieving a complete molecular remission (CMR; disappearance of the BCR::ABL1 transcripts) within the first 3 months of therapy is an important endpoint in newly diagnosed Ph-positive ALL that identifies patients who have an excellent long-term survival and who may not need to receive an allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR). Chemotherapy-free combinations with blinatumomab plus TKIs showed encouraging results with estimated 2 to 4 year overall survival (OS) rates of 80% to 90%. Treatment with blinatumomab and ponatinib resulted in a CMR rate of 84%, a 2-year event-free survival (EFS) of 78%, and a 2-year OS rate of 90%; only 1 patient underwent HSCT. The detection of measurable residual disease (MRD) is the most important factor predicting for disease relapse. Studies have shown that the next-generation sequencing (NGS) assay is more sensitive than RT-PCR for the detection of MRD in Ph-positive ALL. Approximately 15% to 30% of patients who achieve NGS MRD negativity at a sensitivity of 1 × 10-6 may still have detectable BCR::ABL1 transcripts by RT-PCR. Achieving NGS MRD negativity can also identify patients who may have durable remissions with a low risk of relapse. Herein, we discuss the current approach to the management of adults with Ph-positive ALL, the role of HSCT, MRD monitoring, and future therapies.

A Phase 1b Study of Ivonescimab, a Programmed Cell Death Protein-1 and Vascular Endothelial Growth Factor Bispecific Antibody, as First- or Second-Line Therapy for Advanced or Metastatic Immunotherapy-Naive NSCLC.

INTRODUCTION: This study (HARMONi-5) aimed to evaluate the safety and efficacy of ivonescimab (a bispecific antibody against programmed cell death protein 1 and vascular endothelial growth factor) as first- or second-line monotherapy in patients with advanced immunotherapy-naive NSCLC. METHODS: Eligible patients received intravenous ivonescimab 10 mg/kg every 3 weeks (Q3W), 20 mg/kg every 2 weeks (Q2W), 20 mg/kg Q3W, or 30 mg/kg Q3W. The primary end points were safety and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: At data cutoff (October 5, 2022), 108 patients were enrolled and received ivonescimab. Programmed death ligand-1 tumor proportion score (TPS) was greater than or equal to 1% in 74 patients (68.5%), including 35 (32.4%) with TPS greater than or equal to 50%. The median follow-up was 10.4 months (range: 8.4-10.9 mo). For all patients, ORR and disease control rate were 39.8% and 86.1%, respectively. ORR by TPS was 14.7%, 51.4%, and 57.1% in patients with TPS less than 1%, greater than or equal to 1%, and greater than or equal to 50%, respectively. In the 67 programmed death ligand-1-positive patients receiving first-line ivonescimab, the ORR was 33.3%, 52.6%, 60.0%, and 75.0% at the doses of 10 mg/kg Q3W, 20 mg/kg Q2W, 20 mg/kg Q3W, and 30 mg/kg Q3W, respectively. Grade greater than or equal to 3 treatment-related adverse events (TRAEs) were observed in 24 patients (22.2%). TRAEs leading to treatment discontinuation occurred in one patient (0.9%). TRAEs leading to death occurred in three patients (2.8%) with squamous NSCLC. The occurrence of grade greater than or equal to 3 TRAEs and grade greater than or equal to 3 bleeding events in squamous versus nonsquamous NSCLC patients was 25.5% versus 18.9% and 0.0% versus 1.9%, respectively. CONCLUSIONS: Ivonescimab monotherapy was well tolerated and found to have a promising efficacy in patients with advanced or metastatic NSCLC. CLINICALTRIALS: gov identifier: NCT04900363.

Chemotherapy-free approaches to newly-diagnosed acute promyelocytic leukaemia: is oral-arsenic trioxide/all-trans retinoic acid/ascorbic acid the answer?

INTRODUCTION: Acute promyelocytic leukemia (APL) is a distinct form of acute myeloid leukemia characterized by the presence of t(15;17)(q24;21) and the PML:RARA gene fusion. Frontline use of intravenous arsenic trioxide (i.v.-ATO) and all-trans retinoic acid (ATRA) has vastly improved cure rates in APL. Researchers in Hong Kong invented the oral formulation of ATO (oral-ATO) and have confirmed a bioavailability comparable to i.v.-ATO. A plethora of studies have confirmed the safety and efficacy of oral-ATO-based regimens in the frontline and relapsed setting. AREAS COVERED: Aspects on the development of oral-ATO-based regimens for APL in the frontline and relapsed setting are discussed. The short-term and long-term safety and efficacy of oral-ATO-based regimens are discussed. The frontline use of oral-ATO in combination with ATRA and ascorbic acid (AAA) induction in a 'chemotherapy-free' is highlighted. EXPERT OPINION: Current and ongoing data on the use of oral-ATO-based regimens in APL support the use of oral-ATO as an alternative to i.v.-ATO allowing a more convenient and economical approach to the management of APL.

A chemotherapy-free regimen improves prognosis in elderly diffuse large B-cell lymphoma patients with a low-performance status score: A Chinese multi-center real-world study.

Background: Because patients with diffuse large B-cell lymphoma (DLBCL) aged >80 years old typically experience dismal outcomes, it is essential to improve disease control and reduce side effects in such patients. Methods: This was a multi-center retrospective study. Patients aged ≥80 years with pathologically confirmed DLBCL were treated in four centers in the Guangdong province between January 2010 and November 2020. Clinical data from patients receiving different treatment modalities were extracted from electronic medical records. Results: Finally, 50 patients aged ≥80 years were included; four (8.0%) refused treatment, 19 (38%) patients belonged to the chemotherapy-free group, and 27 (54%) patients were in the chemotherapy group. Patients receiving chemotherapy-free treatment had more often a non-germinal center B phenotype than those treated with chemotherapy (P = 0.006). The median progression-free survival (PFS) in the chemotherapy-free group was longer than that in the chemotherapy group (24.7 vs 6.3 months, P = 0.033). Good performance status (PS <2) was associated with higher PFS and overall survival (OS) (P = 0.03; P = 0.02, respectively). In patients with PS of ≥2, the median PFS and OS did not differ between the chemotherapy-free and chemotherapy groups (P = 0.391; P = 0.911, respectively). After stratifying patients with PS <2, the PFS and OS of the chemotherapy-free group were better than those of the chemotherapy group (58.1 vs 7.7 months, P = 0.006; 58.1 vs 26.5 months, P = 0.050). However, treatment-related toxicity did not differ between groups. Conclusion: PS was an independent prognostic factor of elderly DLBCL patients. Accordingly, patients aged ≥80 years with a PS of <2 could benefit from a chemotherapy-free regimen.

Real-world experience with selinexor-containing chemotherapy-free or low-dose chemotherapy regimens for patients with relapsed/refractory acute myeloid leukemia and myeloid sarcoma.

Introduction: Treatment of relapsed or refractory acute myeloid leukemia (R/R AML) and myeloid sarcoma (MS) has presented challenges for decades. Studies on selinexor in combination with various standard or intensive chemotherapy regimens for the treatment of R/R AML have demonstrated promising results. This study aimed to evaluate the efficacy and safety of chemotherapy-free or low-dose chemotherapy regimens with selinexor for R/R AML and MS patients. Methods: Ten patients with R/R AML or MS who received chemotherapy-free or low-dose chemotherapy regimens in combination with selinexor at Tongji Hospital from October 2021 to August 2022 were included in this study. The primary endpoint was overall response rate (ORR) and secondary endpoints included complete remission (CR), CR with incomplete hematological recovery (CRi), partial remission (PR), transplantation rate, and safety. Results: All patients were evaluable for response, achieving CR in four (40.0%) patients and CRi in two (20.0%) patients for a total CR/CRi of 60.0%. The ORR was 80.0% when patients with PR were included. Five (50.0%) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) after treatment with selinexor-containing regimens. At the end of the follow-up, seven (70.0%) patients were alive, and three patients died of transplant-related complications or disease progression. The most frequently reported nonhematologic adverse events (AEs) in patients were grade 1 or 2 asymptomatic hyponatremia. Conclusion: The chemotherapy-free or low-dose chemotherapy regimens in combination with selinexor for R/R AML are feasible and tolerable and provide an opportunity for patients to receive transplantation.

2-4 weeks is the optimal time to operate on colorectal liver metastasis after neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) is generally accepted for treatment of liver metastasis of colorectal cancer (CRLM), but what is a reasonable interval between the latest NAC and surgery is still unknown. The aim of the current study was to investigate the proper timing of surgery after NAC. Subjects were 141 patients with CRLM who underwent NAC and then surgery were retrospectively identified from 2008 to 2020. They were divided into a short interval group (SIG, ≤ 4 weeks) and long interval group (LIG, > 4 weeks) using the software X-tile. The SIG was subclassified group into 3 time periods (1-2 weeks, 2-3 weeks, and 3-4 weeks) to assess the incidence of complications. Patients in the SIG were more likely to have significantly better recurrence-free survival (RFS) (3-year RFS of 47.4% vs. 20.5%, P = 0.043) and no difference in overall survival (OS) (3-year OS 76.1% vs. 79.9%, P = 0.635). The postoperative complication rate was 23.5% in the SIG and 14.0% in the LIG (P = 0.198). The postoperative complication rate in the 1-2 weeks subgroup was marginally higher than that in the > 4 weeks subgroup (35% vs. 14.3% P = 0.055). Multivariate analysis revealed that chemotherapy-free intervals of 1-2 weeks were an independent predictor of increased postoperative complications (OR = 0.263, 95% CI 0.7-0.985 P = 0.048). Patients who underwent surgery within 4 weeks of NAC had better RFS. In addition, 1-2 weeks was an independent factor influencing the development of more complications. For patients with CRLM, performing surgery within 2-4weeks of NAC was feasible and safe, and it did not increase the incidence of postoperative complications but it did prolong RFS.

Case Report: Chemotherapy-free treatment with camrelizumab and anlotinib for elderly patients with KRAS and TP53 mutated advanced lung cancer.

Background: Lung cancer is a major public health issue and an enormous burden on society in China. Most lung cancers occur in elderly patients with non-small cell lung cancer (NSCLC), and many factors limit their treatment options. Chemotherapy-free therapy can avoid psychological fear, treatment pain, and adverse reactions caused by chemotherapy. Patients with non-small cell lung cancer with tumour protein p53 (TP53) gene mutations or Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mutations tend to be more sensitive to anlotinib or programmed cell death protein 1 (PD-1) drugs. However, Kirsten rat sarcoma viral oncogene homologue is a proto-oncogene downstream of the epidermal growth factor receptor (EGFR) gene; therefore, if the Kirsten rat sarcoma viral oncogene homologue gene has an activating mutation, EGFR-targeted drug resistance may occur. Further studies are needed to explore whether patients with dual Kirsten rat sarcoma viral oncogene homologue and tumour protein p53 mutations can be treated with targeted immunotherapy without chemotherapy. Case presentation: A 74-year-old man was referred to the Lanzhou University Second Hospital due to chest tightness, shortness of breath, and weight loss for 2 months and was diagnosed with moderately to poorly differentiated adenocarcinoma. Laboratory examinations showed increased alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen (CA)-125, and CA199 levels, and gene sequencing indicated mutations in Kirsten rat sarcoma viral oncogene homologue and tumour protein p53. Immunohistochemical analysis showed positive PD-L1 and PD-1 expression. Peripheral blood immune checkpoint test using flow cytometry indicated that the PD-1 + CD8 levels were positive. After multi-disciplinary treatment, therapy with a combination of anlotinib and camrelizumab was initiated. Camrelizumab 200 mg was administered intravenously once every 3 weeks. Anlotinib 12 mg was administered orally daily before breakfast for 2 weeks with a week of rest in every cycle of 21 days. A reduction in alpha-fetoprotein, carcinoembryonic antigen, CA125, CA199, and CA724 levels was observed up to the first cycle, which decreased within the normal limits up to the second cycle and continued until the eighteenth cycle. The patient's chest tightness, shortness of breath, weight loss, and other symptoms significantly improved following treatment. Computed tomography imaging showed that the neoplastic lesion was dramatically reduced. The patient is currently being followed-up for more than 2 years to evaluate the duration of the response. Conclusion: Chemotherapy-free immunotherapy combined with targeted therapy is an effective treatment for advanced non-small cell lung cancer in elderly patients with Kirsten rat sarcoma viral oncogene homologue and tumour protein p53 mutations. Such therapies should be supported with further clinical studies with larger sample sizes.

The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades.

Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B Philadelphia chromosome-negative ALL, the integration of blinatumomab and inotuzumab into the frontline therapy has improved the estimated 3-year survival rate to 85% across all risk categories. Our future strategy is to evaluate the early integration of both immunotherapy agents, inotuzumab and blinatumomab, with low-dose chemotherapy (dose-dense mini-Hyper-CVD-inotuzumab-blinatumomab) into the frontline setting followed by CAR T cells consolidation in high-risk patients, without any further maintenance therapy. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year survival rate to 50%. Among patients ≥ 65-70 years, the mortality in complete remission (CR) is still high and is multifactorial (old age, death in CR with infections, development of myelodysplastic syndrome or acute myeloid leukemia). A chemotherapy-free regimen with inotuzumab and blinatumomab is being investigated. The assessment of measurable residual disease (MRD) by next-generation sequencing (NGS) is superior to conventional assays, with early MRD negativity by NGS being associated with the best survival. We anticipate that the future therapy in B-ALL will involve less intensive and shorter chemotherapy regimens in combination with agents targeting CD19 (blinatumomab), CD20, and CD22 (inotuzumab). The optimal timing and use of CAR T cells therapy may be in the setting of minimal disease, and future trials will assess the role of CAR T cells as a consolidation among high-risk patients to replace allogeneic SCT. In summary, the management of ALL has witnessed significant progress during the past four decades. Novel combination regimens including newer-generation BCR::ABL1 TKIs and novel antibodies are questioning the need and duration of intensive chemotherapy and allogeneic SCT.

Low-Intensity and Chemo-Free Treatments in Ph+ ALL: Progression-Free Survival Based on Indirect Comparisons.

In Philadelphia chromosome-positive B-cell (Ph+) acute lymphoblastic leukemia (LLA), growing evidence has accumulated regarding the efficacy of low-intensity and chemo-free regimens. Our objective was to analyze all recent trials evaluating these treatments and to compare them in terms of efficacy. We applied the Shiny method, an artificial intelligence technique, to analyze Kaplan-Meier curves and reconstruct patient-level data. Reconstructed patient data were then evaluated through standard survival statistics and subjected to indirect head-to-head treatment comparisons. The endpoint was progression-free survival (PFS). Based on 432 reconstructed patients, eight trials were analyzed. The survival data from these trials were pooled into three types of treatments: (i) treatments based on tyrosine kinase inhibitors (TKIs) combined with reduced-intensity chemotherapy (denoted as TKICHE); (ii) TKIs associated with steroids with no chemotherapy (TKISTE); (iii) chemotherapy-free combinations of blinatumomab plus TKIs (TKIBLI). According to the Shiny method, the three PFS curves were reported in a single Kaplan-Meier graph and subjected to survival statistics. In terms of PFS, TKIBLI ranked first, TKICHE second, and TKISTE third; the differences between these three regimens were statistically significant. This multi-treatment Kaplan-Meier graph, generated through the Shiny method, summarized the current evidence on these treatments in both qualitative and quantitative terms.