Treatment free remission (TFR) after second-generation tyrosine kinase inhibitors (2G-TKIs) treatment in chronic myeloid leukemia (CML): from feasibility to safety.

INTRODUCTION: Chronic myeloid leukemia (CML) prevalence is currently increasing due to the great efficacy of tyrosine kinase inhibitor (TKI) therapy. Discontinuation of treatment in the long-term, owing to avoid off-target side effects or treatment-free remission (TFR), has become an additional treatment goal in CML patients who achieved a deep molecular response (DMR). Second-generation TKIs (2 G-TKIs) have a significantly higher rate of DMR than imatinib. Hence, especially in young patients with a strategy of TFR, 2 G-TKIs are becoming the most frequently used TKIs and may increase TFR attempts in the future. AREAS COVERED: In this review, the main findings extrapolated from clinical trials and real-life evidence regarding 2 G-TKIs discontinuation were discussed, through broad research on Medline, Embase, and archives from EHA and ASH congresses. EXPERT OPINION: Overall, TFR rate after 2 G-TKIs is ranging from 40% to 60% for selected patients with sustained DMR and it can be considered a safe procedure, that have become, nowadays, a daily practice. However, many crucial aspects regarding treatment choices, timings, as well as predictive factors, patient communication, and optimal strategies need to be better clarified to improve successful TFR rate.

Iberdomide increases innate and adaptive immune cell subsets in the bone marrow of patients with relapsed/refractory multiple myeloma.

Iberdomide is a potent cereblon E3 ligase modulator (CELMoD agent) with promising efficacy and safety as a monotherapy or in combination with other therapies in patients with relapsed/refractory multiple myeloma (RRMM). Using a custom mass cytometry panel designed for large-scale immunophenotyping of the bone marrow tumor microenvironment (TME), we demonstrate significant increases of effector T and natural killer (NK) cells in a cohort of 93 patients with multiple myeloma (MM) treated with iberdomide, correlating findings to disease characteristics, prior therapy, and a peripheral blood immune phenotype. Notably, changes are dose dependent, associated with objective response, and independent of prior refractoriness to MM therapies. This suggests that iberdomide broadly induces innate and adaptive immune activation in the TME, contributing to its antitumor efficacy. Our approach establishes a strategy to study treatment-induced changes in the TME of patients with MM and, more broadly, patients with cancer and establishes rational combination strategies for iberdomide with immune-enhancing therapies to treat MM.

A single-cell atlas characterizes dysregulation of the bone marrow immune microenvironment associated with outcomes in multiple myeloma.

Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies. We generated a transcriptome profile of 1,149,344 single cells from the bone marrow of 263 newly diagnosed patients enrolled in the CoMMpass study and characterized immune and hematopoietic cell populations. Associating cell abundances and gene expression with disease progression revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing patients. Furthermore, signaling analyses suggested active intercellular communication involving APRIL-BCMA, potentially promoting tumor growth and survival. Finally, we demonstrate that integrating immune cell levels with genetic information can significantly improve patient stratification.

Neutrophil to lymphocyte ratio in myelofibrosis patients treated with ruxolitinib may predict prognosis and rate of discontinuation.

BACKGROUND: Myelofibrosis (MF) is a clonal Philadelphia chromosome negative myeloproliferative neoplasm (Ph-MPN). MF is featured by an inflammatory condition that can also drive the progression of disease. Ruxolitinib (ruxo) is the-first-in-class Jak1/2 inhibitor approved for treatment of MF, proved to reduce spleen volume and decrease symptom burden. In various malignancies neutrophil-to-lymphocyte ratio (NLR) has been indicated as predictor of progression free survival (PFS) and overall survival (OS). NLR might reflect the balance between systemic inflammation and immunity and is emerging as a prognostic biomarker in several neoplasms, including the hematological ones. METHODS: We analyzed a cohort of 140 MF patients treated with ruxo to validate baseline NLR (as a continuous variable and as a cut-off 2) as predictor of OS and of ruxo treatment discontinuation. RESULTS: We found that both baseline NLR as a continuous variable [HR 0.8 (95% CI: 0.7-0.9) (p = .006)] and NLR (<2 vs. ≥2) [HR 3.4 (95% CI: 1.6-7.0) (p = .001)] were significantly associated with OS. Censoring for patients undergone allotransplant, baseline NLR <2 was predictive of an earlier ruxo any-other-cause discontinuation [HR 3.7 (95%CI 1.7-8.3) (p < .001)]. CONCLUSIONS: NLR before starting ruxo treatment may be used as a simple and early predictor of OS and earlier ruxo discontinuation in clinical practice.

Sequencing T-cell redirection therapies leads to deep and durable responses in patients with relapsed/refractory myeloma.

T-cell redirection therapy using chimeric antigen receptor (CAR) T cells and bispecific antibodies (BiAbs) has shown promising efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM), leading to the approval of 2 CAR T-cell products and numerous BiAb trials. Data on the outcomes after relapse following BiAbs are urgently required to develop strategies for sequencing salvage therapies. We identified 58 patients progressing after a BiAb trial at Mount Sinai Hospital. Progression-free survival (PFS) to the first salvage (PFS1), second salvage therapy (PFS2), and overall survival (OS) were estimated using the Kaplan-Meier method. The median age of the patients was 67 years, and 78% had high-risk cytogenetics. They had a median of 6 prior therapy lines, 89% were triple-class refractory, and 44% were penta-drug refractory. After the BiAb trial, patients were followed for a median of 30.5 months and received a median of 2 additional salvage therapies (range, 1-9). The most common first salvage was T-cell redirection in 19 patients (10 BiAb and 9 CAR T cells). Ten patients underwent T-cell redirection as a second salvage treatment. T-cell redirection therapy as first or second salvage was feasible and associated with a median PFS1 of 28.9 months, PFS2 of 30.9 months, and an OS of 62% at 2 years. The sequential use of different T-cell redirection therapies is possible and may lead to deep and durable responses following the relapse after BiAb therapy in RRMM.

Asciminib as a third line option in chronic myeloid leukemia.

Unmet needs remain in the treatment of chronic phase chronic myeloid leukemia (CML) in later lines. Sequential use of tyrosine kinase inhibitors (TKIs) is associated with decreased overall survival and emergence of new mutations, particularly the T315I mutation. Among the new drugs developed to overcome resistance and intolerance, the STAMP inhibitor asciminib (which specifically targets the ABL myristoyl pocket) is the first example of a drug that works by allosteric inhibition. This review focuses on its mechanism of action, pharmacokinetic, efficacy, and toxicity, as well as how this drug will change the therapeutic approach for CML patients not eligible to receive other available drugs.

Triple MAPK inhibition salvaged a relapsed post-BCMA CAR-T cell therapy multiple myeloma patient with a BRAF V600E subclonal mutation.

BACKGROUND: Multiple Myeloma (MM) is a progressive plasma cell neoplasm characterized by heterogeneous clonal expansion. Despite promising response rates achieved with anti-BCMA CAR-T cell therapy, patients may still relapse and there are currently no clear therapeutic options in post-CAR-T settings. In this report, we present a case of a post-BCMA CAR-T relapsed/refractory (RR) MM patient with skin extramedullary disease (EMD) in which a novel MAPK inhibition combinatorial strategy was implemented based on next-generation sequencing and in vitro experiments. CASE PRESENTATION: A 61-year-old male with penta-refractory MM penta- (IgA lambda), ISS stage 3 with hyperdiploidy, gain of 1q21 and del13 was treated with anti-BCMA CAR-T cell therapy, achieving a best response of VGPR. He progressed after 6 months and was salvaged for a short period with autologous stem cell transplantation. Eventually, he progressed with extramedullary disease manifested as subcutaneous nodules. Based on whole-exome sequencing, we identified a BRAF (V600E) dominant subclone in both bone marrow and cutaneous plasmacytoma. Following in vitro experiments, and according to our previous studies, we implemented a triple MAPK inhibition strategy under which the patient achieved a very good partial response for 110 days, which allowed to bridge him to subsequent clinical trials and eventually achieve a stringent complete response (sCR). CONCLUSION: Here, we show the applicability, effectiveness, and tolerability the triple MAPK inhibition strategy in the context of post-BCMA CAR-T failure in specific subset of patients. The triple therapy could bridge our hospice bound RRMM patient with BRAF (V600E) to further therapeutic options where sCR was achieved. We will further evaluate triple MAPK inhibition in patients with BRAF V600E in a precision medicine clinical trial launching soon.

Novel therapeutic agents for myelofibrosis after failure or suboptimal response to JAK2 inhbitors.

PURPOSE OF REVIEW: JAK2 inhibitors have changed the therapeutic strategies for the management of primary and secondary myelofibrosis. Ruxolitinib, the first available agent, improved disease-related symptoms, spleen volume, and overall survival compared to conventional chemotherapy. It has been revealed that after 3 years of treatment, about 50% of patients discontinued ruxolitinib for resistance and/or intolerance and should be candidate to a second line of treatment. RECENT FINDINGS: Second-generation tyrosine kinase inhibitors have been tested in this setting, but all these new drugs do not significantly impact on disease progression. Novel agents are in developments that target on different pathways, alone or in combination with JAK2 inhibitors. SUMMARY: In this review, we summarize all the clinical efficacy and safety data of these drugs providing a vision of the possible future.

Pan-Cancer Analysis of Canonical and Modified miRNAs Enhances the Resolution of the Functional miRNAome in Cancer.

Epitranscriptomic studies of miRNAs have added a new layer of complexity to the cancer field. Although there is fast-growing interest in adenosine-to-inosine (A-to-I) miRNA editing and alternative cleavage that shifts miRNA isoforms, simultaneous evaluation of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modification types, including A-to-I miRNA editing and shifted miRNA isoforms, in >13,000 adult and pediatric tumor samples across 38 distinct cancer cohorts from The Cancer Genome Atlas and The Therapeutically Applicable Research to Generate Effective Treatments data sets. The differences between canonical miRNAs and the wider miRNAome in terms of expression, clustering, dysregulation, and prognostic standpoint were investigated. The combination of canonical miRNAs and modified miRNAs boosted the quality of clustering results, outlining unique clinicopathologic features among cohorts. Certain modified miRNAs showed opposite expression from their canonical counterparts in cancer, potentially impacting their targets and function. Finally, a shifted and edited miRNA isoform was experimentally validated to directly bind and suppress a unique target. These findings outline the importance of going beyond the well-established paradigm of one mature miRNA per miRNA arm to elucidate novel mechanisms related to cancer progression. SIGNIFICANCE: Modified miRNAs may act as cancer biomarkers and function as allies or antagonists of their canonical counterparts in gene regulation, suggesting the concurrent consideration of canonical and modified miRNAs can boost patient stratification.

A Three-Gene Signature Predicts Response to Selinexor in Multiple Myeloma.

PURPOSE: Selinexor is the first selective inhibitor of nuclear export to be approved for the treatment of relapsed or refractory multiple myeloma (MM). Currently, there are no known genomic biomarkers or assays to help select MM patients at higher likelihood of response to selinexor. Here, we aimed to characterize the transcriptomic correlates of response to selinexor-based therapy. METHODS: We performed RNA sequencing on CD138+ cells from the bone marrow of 100 patients with MM who participated in the BOSTON study, followed by differential gene expression and pathway analysis. Using the differentially expressed genes, we used cox proportional hazard models to identify a gene signature predictive of response to selinexor, followed by validation in external cohorts. RESULTS: The three-gene signature predicts response to selinexor-based therapy in patients with MM in the BOSTON cohort. Then, we validated this gene signature in 64 patients from the STORM cohort of triple-class refractory MM and additionally in an external cohort of 35 patients treated in a real-world setting outside of clinical trials. We found that the signature tracks with both depth and duration of response, and it also validates in a different tumor type using a cohort of pretreatment tumors from patients with recurrent glioblastoma. Furthermore, the genes involved in the signature, WNT10A, DUSP1, and ETV7, reveal a potential mechanism through upregulated interferon-mediated apoptotic signaling that may prime tumors to respond to selinexor-based therapy. CONCLUSION: In this study, we present a present a novel, three-gene expression signature that predicts selinexor response in MM. This signature has important clinical relevance as it could identify patients with cancer who are most likely to benefit from treatment with selinexor-based therapy.

Software Workflows and Infrastructures for Precision Oncology.

Precision oncology mainly relies on genetic and molecular patient profiling from high-throughput sequencing data. The necessity to process and analyze large volumes of data has led to the development of robust computational tools and methods. The most challenging aspect in the implementation of a precision oncology workflow involves proper handling of large volume of data, while ensuring the results are reproducible and replicable. In this chapter, we provide a detailed description of the various tools available for the design and implementation of a precision oncology pipeline along with the technical considerations to make to utilize these tools effectively. We then provide a guide to the development of a precision oncology pipeline, with a specific emphasis on the software workflows and infrastructure needed.

The Architecture of a Precision Oncology Platform.

Precision oncology is a novel research field and approach to cancer care which leverages high-throughput sequencing technologies and bioinformatics pipelines to determine diagnosis, prognosis, and treatment of patients in a personalized manner. This chapter provides an overview of a typical precision oncology software platform, from raw data to patient reports. Standard and advanced analytical components are described and discussed, along with their strengths and limitations, in general and in the context of a precision oncology application for advanced cancer patients.

Computational Approaches for the Investigation of Intra-tumor Heterogeneity and Clonal Evolution from Bulk Sequencing Data in Precision Oncology Applications.

While the clonal model of cancer evolution was first proposed over 40 years ago, only recently next-generation sequencing has allowed a more precise and quantitative assessment of tumor clonal and subclonal landscape. Consequently, a plethora of computational approaches and tools have been developed to analyze this data with the goal of inferring the clonal landscape of a tumor and characterize its temporal or spatial evolution. This chapter introduces intra-tumor heterogeneity (ITH) in the context of precision oncology applications and provides an overview of the basic concepts, algorithms, and tools for the dissection, analysis, and visualization of ITH from bulk DNA sequencing.

Artificial Intelligence for Precision Oncology.

Precision oncology is an innovative approach to cancer care in which diagnosis, prognosis, and treatment are informed by the individual patient's genetic and molecular profile. The rapid development of novel high-throughput omics technologies in recent years has led to the generation of massive amount of complex patient data, which in turn has prompted the development of novel computational infrastructures, platforms, and tools to store, retrieve, and analyze this data efficiently. Artificial intelligence (AI), and in particular its subfield of machine learning, is ideal for deciphering patterns in large datasets and offers unique opportunities for advancing precision oncology. In this chapter, we provide an overview of the various public data resources and applications of AI in precision oncology and cancer research, from subtype identification to drug prioritization, using multi-omics datasets. We also discuss the impact of AI-powered medical image analysis in oncology and present the first diagnostic FDA-approved AI-powered tools.

Single-Cell Sequencing Technologies in Precision Oncology.

Single-cell sequencing technologies are revolutionizing cancer research and are poised to become the standard for translational cancer studies. Rapidly decreasing costs and increasing throughput and resolution are paving the way for the adoption of single-cell technologies in clinical settings for personalized medicine applications. In this chapter, we review the state of the art of single-cell DNA and RNA sequencing technologies, the computational tools to analyze the data, and their potential application to precision oncology. We also discuss the advantages of single-cell over bulk sequencing for the dissection of intra-tumor heterogeneity and the characterization of subclonal cell populations, the implementation of targeted drug repurposing approaches, and describe advanced methodologies for multi-omics data integration and to assess cell signaling at single-cell resolution.

Multi-Omics Profiling of the Tumor Microenvironment.

All solid tumors and many hematological malignancies grow and proliferate in a tumor microenvironment (TME), a spectrum of continuous and highly dynamic interactions with different immune and stromal cells. This ecosystem contributes to the extensive heterogeneity that exists between and within cancer patients. Understanding the characteristics of this intricate network could significantly improve cancer prognosis, as was demonstrated already for a subset of patients by the advent of immunotherapies (including monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor (CAR) T cells. The development of multimodal omics technologies has allowed researchers to document and characterize the TME at single-cell resolution, which provides an unprecedent opportunity to understand the full complexity of the tumor microenvironment. In this chapter, we highlight the paradigm shift that has brought the TME to the forefront of cancer research and discuss its composition. In addition, we summarize the available multimodal single-cell omics methods that allow studying the TME from different angles, as well as their advantages and limitations. We discuss computational analysis tools, data integration, and methods to specifically study crosstalk between TME components. Finally, we touch upon the implications of studying the TME for ongoing or future clinical studies and how these can lead to more effective treatments for cancer patients.

Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy.

B-cell maturation antigen (BCMA) is a prominent tumor-associated target for chimeric antigen receptor (CAR)-T cell therapy in multiple myeloma (MM). Here, we describe the case of a patient with MM who was enrolled in the CARTITUDE-1 trial ( NCT03548207 ) and who developed a progressive movement disorder with features of parkinsonism approximately 3 months after ciltacabtagene autoleucel BCMA-targeted CAR-T cell infusion, associated with CAR-T cell persistence in the blood and cerebrospinal fluid, and basal ganglia lymphocytic infiltration. We show BCMA expression on neurons and astrocytes in the patient's basal ganglia. Public transcriptomic datasets further confirm BCMA RNA expression in the caudate of normal human brains, suggesting that this might be an on-target effect of anti-BCMA therapy. Given reports of three patients with grade 3 or higher parkinsonism on the phase 2 ciltacabtagene autoleucel trial and of grade 3 parkinsonism in the idecabtagene vicleucel package insert, our findings support close neurological monitoring of patients on BCMA-targeted T cell therapies.