Connective tissue disease (CTD) is a kind of autoimmune disease with multisystem damage that mainly involves the bone, muscle and the vascular system. Patients with CTD have an increased incidence of malignant tumors, particularly hematological malignancies, compared to the general population. This association of autoimmune diseases with lymphoproliferative diseases is bidirectional. There is a heightened risk of B-cell lymphoma development among patients with CTD, and patients with autoimmune disease display a higher prevalence of non-Hodgkin lymphoma compared to the general population. More than 80% of malignant tumours occur after or at the same time as CTD develops. Among secondary lymphomas, the most common aggressive type of lymphoma is diffuse large B-cell lymphoma, while the most common indolent type is marginal zone lymphoma. Novel targets in patients with B-cell lymphoma are BCL2, the NF-κB pathway, components of the BCR activator of RhoGEF and GTPase signalling pathway and the PI3K-mTOR pathway. In this review, information is provided on the common types of B-cell lymphoma in CTD, the pathogenic factors implicated in lymphoma development and recent advancements in therapies effective for both autoimmune conditions and malignant lymphoproliferative diseases.

Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL) in Japan, the United States, and Western Europe. Parsaclisib is a potent, selective next-generation PI3Kδ inhibitor that has demonstrated clinical efficacy and tolerability in phase II studies of patients with relapsed or refractory (R/R) B-cell NHL, including FL. We report results from CITADEL-213 (NCT04434937), a phase II study evaluating the efficacy and safety of parsaclisib in Japanese patients with R/R FL. Eligible patients were aged ≥ 18 years with histologically confirmed R/R FL (grade 1, 2, or 3a), had received two or more prior systemic therapies, and were ineligible for hematopoietic stem cell transplantation. Patients received parsaclisib 20 mg once daily for 8 weeks, followed by parsaclisib 2.5 mg once daily thereafter. The primary endpoint was the objective response rate (ORR). At the data cut-off (February 16, 2023), 42 patients had received treatment with parsaclisib, of whom 41 were evaluable for change in target tumor size. Median (range) age at baseline was 66.5 (52-87) years. ORR (95% confidence interval [CI]) was 88.1% (74.4-96.0), with 10 patients (23.8%) experiencing a complete response and 27 patients (64.3%) experiencing a partial response. Median (95% CI) duration of response was not reached (8.0 months-not estimable). The most common treatment-emergent adverse events (TEAEs) were diarrhea (28.6%; grade ≥ 3, 7.1%) and stomatitis (23.8%; grade ≥ 3, 11.9%); TEAEs led to parsaclisib discontinuation in five patients (11.9%). There were no fatal TEAEs. In conclusion, parsaclisib monotherapy demonstrated durable responses with a manageable safety profile in Japanese patients with R/R FL. Trial Registration: ClinicalTrials.gov, NCT04434937.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous subtype of non-Hodgkin lymphoma, with two-thirds of patients relapsing or resisting existing therapies, highlighting the urgent need for effective treatments. Toosendanin (TSN), a triterpenoid from Meliae Cortex, exhibits significant anti-cancer activity by modulating cell survival and proliferation. This study investigates the anti-lymphoma effects and underlying mechanisms of TSN, proposing it as a potential therapeutic agent to address the challenges of DLBCL. Network pharmacology, molecular docking, and transcriptome sequencing were employed to predict TSN's anti-DLBCL potential. Findings were validated through in vitro and in vivo experiments, including cell viability assays, flow cytometry, quantitative PCR, Western blotting, reverse experiments with small-molecule inhibitors or genetic editing, and a cell-derived xenograft (CDX) model. Bioinformatics analyses revealed TSN's strong binding affinity to PI3Kα/β and Polo-like kinase 1 (PLK1). Experiments showed that TSN downregulated the PI3K/Akt signaling pathway and reduced PLK1 mRNA and protein levels, inducing apoptosis, cell cycle arrest, and cell death in DLBCL cells. RNA sequencing and metabolic assays indicated TSN upregulated cholesterol biosynthesis in DLBCL cells. Co-treatment with a statin enhanced TSN's anti-DLBCL effects while mitigating hepatic and pulmonary toxicity. This study identifies TSN as a dual inhibitor of PI3K and PLK1 with significant therapeutic potential for DLBCL. It also proposes a lipid-modulating strategy to enhance TSN's cytotoxicity while reducing adverse effects, offering a promising approach to improve DLBCL treatment outcomes.

Follicular lymphoma (FL) is the most common type of indolent lymphoma, and the prognosis is favorable for most patients. However, FL remains generally incurable, and relapse is common. Patients are at risk of developing treatment-resistant lymphoma, particularly when early disease progression occurs or transformation to aggressive lymphoma takes place. Furthermore, lymphoma is the leading cause of death among patients with FL, emphasizing the need for more effective treatment strategies. This review summarizes therapeutic approaches for FL, with a focus on therapies currently in development. Recent biological insights have driven the emergence of highly effective treatments, including novel immune and targeted therapies. Clinical trials are assessing the efficacy of these novel approaches, which are increasingly used in earlier line settings. In the future, FL therapy is expected to rely less on chemotherapeutic methods, extend remission, and potentially enable cures for a growing number of patients.

T cell large granular lymphocytic leukemia (T-LGLL) is a clonal lymphoproliferative disorder, originated from mature effector memory CD8+ T cells. It is a challenge to define the leukemic T cell clones due to the lack of definite markers. Here, we decipher the heterogeneity of CD8+ T cells using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and T cell receptor (TCR) profiling in T-LGLL patients. A CD8+ terminal effector subset is identified, marked by reduced KLRG1 expression. Remarkably, high fidelity of leukemic clonality was specially limited in KLRG1- large granular lymphocytes (LGLs), not seen in KLRG1+ LGLs in T-LGLL patients or in KLRG1- LGLs in healthy controls. KLRG1- leukemic LGLs show upregulated PI3K signaling with enhanced cytotoxicity and exhaustion, persisting after conventional treatment. In a pilot trial of linperlisib (a PI3Kδ inhibitor) for refractory cases, 7 of 8 participants quickly respond with satisfactory safety. This study is registered at ClinicalTrials.gov (NCT05676710).

Marginal zone lymphoma (MZL) is a rare subtype of non-Hodgkin lymphoma, and its diagnosis primarily relies on pathological biopsy. The study aims to investigate the causal relationships between 41 inflammatory cytokines and MZL using a two-sample bidirectional Mendelian randomization (MR) approach, providing new insights and methodologies for rapid differential diagnosis and treatment strategies.

Causal associations between 41 inflammatory cytokines and MZL were examined using genetic variant data from two large-scale genome-wide association studies. The inverse variance weighting method was employed, and multiple sensitivity analyses, including MR-Egger, weighted median, simple model, and weighted model methods, were conducted to strengthen the robustness of the findings.

Elevated levels of MIG and IL-10 were associated with an increased risk of MZL (MIG: OR = 1.57, p = 0.035; IL-10: OR = 1.69, p = 0.021), while higher B-NGF levels exhibited a protective effect (OR = 0.46, p = 0.027). Reverse MR analysis revealed a negative correlation between MZL and IFN-γ levels (OR = 0.97, p = 0.015).

MIG, IL-10, B-NGF, and IFN-γ are potential biomarkers and therapeutic targets for MZL. IFN-γ likely acts as a downstream molecule in MZL pathogenesis, offering novel insights into MZL-related research, clinical diagnosis, and treatment strategies.

Although chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are the same biologic disease entity and warrant identical treatment approaches, patients with SLL have frequently been excluded from clinical trials in CLL.

This study assessed the representation of patients with SLL among Phase II or III clinical trials cited in the 2024 National Comprehensive Cancer Network (NCCN) treatment guidelines.

Patients with SLL were explicitly eligible for only 21 (38%) of the 56 clinical trials for CLL, comprising 222 (6%) of the 3440 enrolled patients. Notably, 380 patients with SLL were enrolled in 16 separate non-CLL clinical trials alongside patients with indolent B-cell lymphomas such as follicular lymphoma. In CLL trials, patients with SLL were included in a greater proportion of studies evaluating BTK inhibitors (67%) or BTK/BCL2 inhibitor combinations (67%) compared to BCL2 inhibitors (0%) or chemoimmunotherapy (0%).

Although recent and upcoming trials show a promising trend toward the inclusion of patients with SLL, further advocacy is needed to raise awareness of the biological similarities between CLL and SLL and to promote the representation of patients with SLL in CLL/SLL clinical research.

Follicular lymphoma is the most prevalent form of indolent B-cell lymphoma, characterized by gradual disease progression and potential survival over several decades. Although the overall prognosis is typically favorable, some patients remain at risk for disease progression or transformation into a more aggressive variant. Recent advancements in the treatment of relapsed or refractory follicular lymphoma include cereblon modulators, kinase inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and antibody-drug conjugates. Ongoing research into novel prognostic markers may improve the identification of patients at high risk for early progression, multiple relapses, or histological transformation, facilitating more precise and individualized treatment strategies.

Bronchial asthma is a complex and heterogeneous disease with ongoing airway inflammation and increased airway responsiveness. Key characteristics of the disease include persistent airway inflammation, airway hyperresponsiveness, and airway remodeling. Asthma's chronic and recurrent characteristics contribute to airway remodeling and inflammation, which can exacerbate lung damage. Presently, inflammation is predominantly managed with corticosteroids, yet there is a notable absence of treatments specifically addressing airway remodeling. The phosphoinositide 3-kinase (PI3K) signaling pathway is integral to the processes of inflammation, airway remodeling, and immune responses. Pharmacological agents targeting this pathway are currently undergoing clinical evaluation. This review elucidates the role of PI3K in the immune responses, airway inflammation, and remodeling associated with asthma, examining its underlying mechanisms. Furthermore, we synthesize the existing literature on the therapeutic potential of PI3K inhibitors for asthma management, emphasizing immune modulation, airway inflammation, and remodeling, including drug development and ongoing clinical trials. Lastly, we explore how various PI3K-targeted therapies may enhance efficacy and improve tolerance.

Zandelisib, a selective, potent PI3Kδ inhibitor, demonstrated favourable outcomes in patients with relapsed or refractory follicular lymphoma in a global phase II study. This phase II study evaluated the efficacy and safety of zandelisib for relapsed or refractory follicular lymphoma or marginal zone lymphoma. Sixty-one patients received zandelisib orally at 60 mg daily continuously in the first two 28-day cycles, followed by intermittent dosing on Days 1-7 following each cycle until progressive disease or unacceptable toxicity. Objective and complete response rates were 75.4% (95% confidence interval [CI], 62.7%-85.5%) and 24.6% (95% CI, 14.5%-37.3%) respectively. Median time to response was 58 days; 70.5% (43/61) of patients achieved their first response by Week 8. At least one Grade ≥ 3 treatment-emergent adverse event (TEAE) occurred in 55.7% of patients: transaminase elevation (8.2%); cutaneous reactions (3.3%); and diarrhoea, enterocolitis and lung infection (1.6% each), defined as adverse events of special interest. The discontinuation rate due to any TEAE was 14.8%. No zandelisib-related death occurred. Zandelisib showed favourable efficacy and tolerability in Japanese patients with relapsed or refractory indolent non-Hodgkin B-cell lymphoma. This unique dosing schedule may maintain efficacy while mitigating the safety issues observed with other PI3Kδ inhibitors (ClinicalTrials.gov number, NCT04533581).

The management of marginal zone lymphoma (MZL), an indolent B-cell non-Hodgkin lymphoma, requires a personalized and adaptive approach due to its clinical and prognostic heterogeneity. We believe treatment should emphasize a balanced strategy considering the subtype, disease burden, symptoms, and actionable genetic or environmental factors, such as infections or autoimmune diseases. For asymptomatic patients with low tumor burden or disseminated disease, a watch-and-wait approach remains appropriate, given MZL's indolent nature and the risks of overtreatment. Conversely, for symptomatic or high-burden cases, early intervention with chemoimmunotherapy is recommended for effective disease control. Surgery remains essential for both diagnosis and the treatment of localized disease. Incorporating molecular profiling and prognostic models, such as MZL-IPI and POD24, is crucial for decision-making and risk stratification. Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients. With ongoing advancements in understanding dysregulated signaling pathways and the tumor microenvironment, we anticipate novel targeted therapies and combination regimens will further improve outcomes. We advocate for molecular testing at diagnosis to identify actionable biomarkers, particularly for patients with refractory or relapsed disease. Finally, MZL management requires vigilant follow-up with adjustments based on evolving disease features. Treatment decisions should integrate patient preferences, clinical context, and the latest evidence to maximize survival while preserving quality of life.

Over the past two decades, there has been a continuous improvement in outcome for patients with indolent lymphoma (iNHL) resulting in a gradual accumulation of survivors. While life expectancy in the current era approaches that of the lymphoma-free population, patients continue to experience lifelong complications of the disease and its treatment affecting general health, emotional, psychological and social wellbeing, relationships, employment, finances, and fitness. Contemporary care models while suited to the management of lymphoma are often lacking when it comes to identification and management of these additional needs. Given improvements in physical survival achieved over the past decades, it is timely for us to focus on other issues affecting patient wellbeing including immunodeficiency and infection, second cancers, cardiovascular disease, bone health, psychological wellbeing, and sexual health. Many of these aspects are in the domain of the primary care physician; however, there is limited guidance on how these issues should be addressed. It is now time for us to engage our patients, their caregivers, and other healthcare providers in care aspects beyond the lymphoma diagnosis, so they can anticipate a rich and full life, free from both direct and indirect consequences of the lymphoma diagnosis.

Activated PI3K delta syndrome (APDS) is a primary immunodeficiency that is caused by mutations in the PI3K signalling pathway resulting in either gain-of-function or loss-of-function phenotypes of APDS 1 and 2. Malignancy is one of the most serious complications associated with APDS patients, with the most commonly occurring of these being lymphoma, and is the most common cause of death in APDS patients. Management of APDS is complex and variable due to the heterogeneous nature of the disease and ranges from antimicrobial and immunosuppressant agents to haematopoetic stem cell transplantation. More recently, an increasing level of interest has been shown in the use of more targeted agents such as PI3Kδ-specific inhibitors. Here, we provide expert perspective on the suspected causality of a case of lymphoma observed in a 20-year-old female patient who was included in a clinical trial of leniolisib, a PI3K inhibitor.

Follicular lymphoma (FL) is the second most common type of lymphoma (20% of all non-Hodgkin lymphomas), derived from germinal centre (GC) B cells, and is characterised by its significant clinical, prognostic and biological heterogeneity, leading to complexity in management. Despite significant biological investigation and indisputable clinical progress since the advent of the immunotherapy era more than 20 years ago, much remains to be done to understand and cure this lymphoma. Today, FL is metaphorically a giant puzzle on the table with patches of sky, landscape and foliage clearly appearing. However, many of the remaining pieces are held by various stakeholders (e.g. clinicians, pathologists, researchers, drug developers) without global agreement on what the gaps are, or any clear blueprint on how to solve the puzzle of understanding the heterogeneity of this disease and create curative and tailored therapies. With the advent of new investigation and drug technologies, together with recent advances in our capacity to manage big data, the time seems ripe for a change of scale. More than ever, this will require collaboration between and within all stakeholders to overcome the current bottlenecks in the field. As for every investigator, we acknowledge that this first draft is necessarily biased, incomplete and some FL expert readers might recognise some remaining gaps not addressed. We hope they will reply to make this effort a collaborative one to assemble all the pieces in the most ideal fashion. As such, this review intends to be a first step and an interactive platform to a collaborative roadmap towards better understanding and care of FL.

Relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) is generally considered incurable with current treatment options. Previous phase 1b/2 results showed combining magrolimab (anti-cluster-of-differentiation [CD] 47 antibody) with the anti-CD20 antibody rituximab (M+R) has antitumor activity against R/R iNHL. We report 3-year follow-up data from this phase 1b/2 study assessing long-term safety and efficacy of M+R in R/R iNHL. After magrolimab priming, 4 patient groups in phase 1b M+R received 10 to 45-mg/kg magrolimab doses with 375 mg/m2 rituximab. Phase 2 explored 30 and 45 mg/kg magrolimab. Primary end points were treatment-emergent adverse events (TEAEs) and objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory analysis included circulating tumor DNA, biomarkers of magrolimab tumor penetration, and drug target expression assessments. Of 46 patients treated in phase 1b/2, 42 had follicular lymphoma and 4 had marginal zone lymphoma. All patients experienced ≥1 any-grade TEAE, and 44 reported ≥1 treatment-related TEAE. No additional toxicities were reported during long-term follow-up, and there were no treatment-related deaths. Median follow-up was 36.7 (range, 1.2-62.3) months. The ORR was 52.2%, with 30.4% achieving a complete response. The median DOR was 15.9 months, and median time-to-response was 1.8 months. Median PFS and OS were 7.4 (95% confidence interval, 4.8-13.0) months and not reached, respectively. These results demonstrate the long-term safety and efficacy of M+R in patients with iNHL and support further exploration of CD47-based treatment combinations. This trial was registered at www.ClinicalTrials.gov as #NCT02953509.

Lymphoma is the sixth most prevalent cancer globally. Non-Hodgkin's lymphomas are the majority group of lymphomas, with B cells accounting for approximately 95% of these lymphomas. A key feature of B-cell lymphoma is the functional perturbations of essential biological pathways caused by genetic aberrations. These lead to atypical gene expression, providing cells with a selective growth advantage. Molecular analysis reveals that each lymphoma subtype has unique molecular mutations, which pose challenges in disease management and treatment. Substantial efforts over the last decade have led to the integration of this information into clinical applications, resulting in crucial insights into clinical diagnosis and targeted therapies. However, with the growing need for more effective medication development, we anticipate a deeper understanding of signaling pathways and their interactions to emerge. This review aims to demonstrate how the BCR, specific signaling pathways like PI3K/AKT/mTOR, NF-kB, and JAK/STAT are diverse in common types of B-cell lymphoma. Furthermore, it offers a detailed examination of each pathway and a synopsis of the approved or in-development targeted therapies. In conclusion, finding the activated signaling pathways is crucial for developing effective treatment plans to improve the prognosis of patients with relapsed or refractory lymphoma. Trial Registration: ClinicalTrials.gov identifier: NCT02180724, NCT02029443, NCT02477696, NCT03836261, NCT02343120, NCT04440059, NCT01882803, NCT01258998, NCT01742988, NCT02055820, NCT02285062, NCT01855750, NCT03422679, NCT01897571.

An increasing number of newer targeted oncologic therapies approved for clinical use can cause drug-related pneumonitis. Drug-related pneumonitis can be difficult to diagnose and requires a high index of suspicion. This review serves as an update to a prior review in this journal about pneumonitis with precision oncology therapies. In this review, we focus on the incidence, timing of onset, and imaging patterns of pneumonitis associated with a number of newly approved precision oncologic agents, with a particular focus on new antibody-drug conjugate therapies.

Marginal Zone Lymphoma (MZL) and Waldenström's Macroglobulinemia (WM) are indolent lymphomas that both arise from post germinal center lymphocytes. Both can secrete a monoclonal protein but high levels are mostly only seen in WM. The MYD88 L256P somatic mutation that is present in an estimated 95% of patients with WM has helped greatly in differentiating the two lymphomas. Several large clinical studies with new drugs have been performed that have provided new treatment options for both MZL and WM patients. In this short review we will discuss the recent literature published and provide some recommendations.

Phosphatidylinositol 3-kinase (PI3K) inhibitors transformed management of various malignancies. This study preclinically characterized TQ-B3525 (dual PI3Kα/δ inhibitor) and assessed the recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics in relapsed or refractory (R/R) lymphoma or advanced solid tumors (STs).

Oral TQ-B3525 was given at eight dose levels on a 28-day cycle. Primary end points were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and safety.

TQ-B3525 showed high selectivity and suppressed tumor growth. Between June 12, 2018, and November 18, 2020, 80 patients were enrolled (63 in dose-escalation cohort; 17 in dose-expansion cohort). Two DLTs occurred in two (two of 63, 3.2%) DLT-evaluable patients; MTD was not identified. TQ-B3525 at 20 mg once daily was selected as RP2D. Grade 3 or worse treatment-related adverse events mainly included hyperglycemia (16.3%), neutrophil count decreased (15.0%), and diarrhea (10.0%). Two (2.5%) treatment-related deaths were reported. Sixty patients with R/R lymphoma and 11 advanced STs demonstrated objective response rates of 68.3% and 9.1%, disease control rates of 91.7% and 54.6%, median progression-free survivals of 12.1 and 1.1 months; median overall survivals were not reached.

TQ-B3525 exhibited rapid absorption and a nearly proportional increase in exposure. Acceptable safety and promising efficacy support further investigation of TQ-B3525 (20 mg once daily) for R/R lymphoma.

Bruton's tyrosine kinaseinhibitors (BTKis) changed the trajectory of upfront and relapsed/refractory chronic lymphocytic leukemia (CLL) treatment. However, BTKis are plagued by a spectrum of toxicities. Zanubrutinib was developed to circumvent challenges with prolonged tolerability by increasing BTK selectivity and maximizing efficacy through pharmacokinetic/pharmacodynamic optimization. However, with the availability of ibrutinib, acalabrutinib, and zanubrutinib, limited data exists to guide sequencing of BTKi therapy in the relapsed/refractory setting.

We review the first head-to-head trial (ALPINE) of zanubrutinib versus ibrutinib for the treatment of relapsed/refractory CLL and compare zanubrutinib's clinical efficacy and toxicities, including in patients with del(17p) and/or TP53 mutations to ibrutinib and acalabrutinib.

Zanubrutinibrepresents one of the new standards of care for relapsed/refractory CLL based on superior progression-free survival and response rates over ibrutinib. Whilezanubrutinib is associated with fewer cardiac toxicities, similar rates of neutropenia and hypertension are noted. Ongoing studies are pushing the envelope, utilizing targeted drug combinations and minimal residual disease markers as well as receptor tyrosine kinase-like orphan receptor 1 inhibitors, chimeric antigen receptor T-cells, and novel BTK degraders. However, zanubrutinibrepresents a strong contender in the arsenal of treatment options for relapsed/refractory CLL.

Type 2 diabetes mellitus (T2DM) and cancer share common risk factors including obesity, inflammation, hyperglycemia, and hyperinsulinemia. High insulin levels activate the PI3K/Akt/mTOR signaling pathway promoting cancer cell growth, survival, proliferation, metastasis, and anti-apoptosis. The inhibition of the PI3K/Akt/mTOR signaling pathway for cancer remains a promising therapy; however, drug resistance poses a major problem in clinical settings resulting in limited efficacy of agents; thus, combination treatments with therapeutic inhibitors may solve the resistance to such agents. Understanding the metabolic link between diabetes and cancer can assist in improving the therapeutic strategies used for the management of cancer patients with diabetes and vice versa. This review provides an overview of shared molecular mechanisms between diabetes and cancer as well as discusses established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management.

The Phosphoinositide 3-kinases (PI3Ks) family plays a crucial role in tumorigenesis. Alpelisib (inhibiting PI3Kα), copanlisib (inhibiting PI3Kα andPI3Kδ), duvelisib (inhibiting PI3Kδ and PI3Kγ), and idelalisib (inhibiting PI3Kδ) were developed to target the PI3K pathway. However, the toxicity limits their application to some extent. It's necessary to investigate the adverse effects (AEs) of these inhibitors.

We conducted a comparative analysis of the safety signals of AEs in PI3K inhibitors using disproportionality analysis in the FDA Adverse Event Reporting System database(FAERS).

Our study identified significant safety signals for metabolic disorders with all PI3K inhibitors. Notable safety signals for gastrointestinal disorders were observed with most PI3K inhibitors, with the exception of copanlisib. Common AEs shared among all PI3K inhibitors included colitis and dehydration. Alpelisib displayed unique AEs associated with metabolic disorders, whereas copanlisib exhibited idiosyncratic AEs linked to cardiac and vascular disorders. Stevens-Johnson syndrome emerged as a common severe adverse event (SAE) among alpelisib, copanlisib, and idelalisib, while febrile neutropenia was prevalent among copanlisib, duvelisib, and idelalisib. Intestinal perforation was solely associated with alpelisib.

The safety profiles of the five PI3K inhibitors vary concerning adverse events. These findings could guide drug selection and inform future prospective research.

The PI3K signaling pathway regulates key cellular processes and is one of the most aberrantly activated pathways in cancer. The class I PI3K catalytic subunits p110γ and p110δ are highly enriched in leukocytes, providing an additional rationale for targeting these PI3Ks in hematologic malignancies. In 2014, the PI3Kδ inhibitor idelalisib was the first of four PI3K inhibitors (PI3Ki) to receive regulatory approval for relapsed B-cell malignancies. This was followed by approvals of the pan-class I inhibitor copanlisib (2017), the dual PI3Kγ/δ inhibitor duvelisib (2018), and the PI3Kδ and casein kinase 1ε inhibitor umbralisib (2021). Copanlisib and umbralisib received accelerated approvals, whereas idelalisib and duvelisib received initial accelerated approvals followed by full approvals. The accelerated approvals were based on overall response rates; however, follow-up studies showed increased risk of death and serious side effects. Furthermore, the confirmatory trial with copanlisib failed to show an improvement in progression-free survival when compared with chemoimmunotherapy. These developments led to black box warnings for idelalisib and duvelisib and withdrawal of copanlisib and umbralisib from the market by their manufacturers. Given the uncertain future of this drug class, additional manufacturers terminated ongoing phase III trials with novel PI3Kis. In this study, we review the development and current status of PI3Kis in hematology, limitations to their use, and our perspective on whether there is a future for PI3Kis in hematology.

PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 .

The dysregulation of kinases has emerged as a major class of targets for anticancer drug discovery given its node roles in the etiology of tumorigenesis, progression, invasion, and metastasis of malignancies, which is validated by the FDA approval of 28 small molecule kinase inhibitor (SMKI) drugs for cancer treatment at the end of 2015. While the preclinical and clinical data of these drugs are widely presented, it is highly essential to give an updated review on the medical indications, design principles and binding modes of these anti-tumor SMKIs approved by the FDA to offer insights for the future development of SMKIs with specific efficacy and safety.

Genome sequencing has revealed frequent mutations in Ras homolog family member A (RHOA) among various cancers with unique aberrant profiles and pathogenic effects, especially in peripheral T-cell lymphoma (PTCL). The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type, thereby leading to different functional and biological properties, which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors. However, the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated. Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways. The promising potential of targeting RHOA as a therapeutic modality is also outlined. This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.

The phosphatidylinositol-4,5-bisphosphate 3-kinase delta isoform (Pik3cd), usually considered immune-specific, was unexpectedly identified as a gene potentially related to either regeneration and/or differentiation in animals lacking hepatocellular Integrin Linked Kinase (ILK). Since a specific inhibitor (Idelalisib, or CAL101) for the catalytic subunit encoded by Pik3cd (p110δ) has reported hepatotoxicity when used for treating chronic lymphocytic leukemia and other lymphomas, the authors aimed to elucidate whether there is a role for p110δ in normal liver function. To determine the effect on normal liver regeneration, partial hepatectomy (PHx) was performed using mice in which p110δ was first inhibited using CAL101. Inhibition led to over a 50% decrease in proliferating hepatocytes in the first 2 days after PHx. This difference correlated with phosphorylation changes in the HGF and EGF receptors (MET and EGFR, respectively) and NF-κB signaling. Ingenuity Pathway Analyses implicated C/EBPβ, HGF, and the EGFR heterodimeric partner, ERBB2, as three of the top 20 regulators downstream of p110δ signaling because their pathways were suppressed in the presence of CAL101 at 1 day post-PHx. A regulatory role for p110δ signaling in mouse and rat hepatocytes through MET and EGFR was further verified using hepatocyte primary cultures, in the presence or absence of CAL101. Combined, these data support a role for p110δ as a downstream regulator of normal hepatocytes when stimulated to proliferate.

In this global phase 2 study in patients with relapsed/refractory follicular lymphoma (FL), zandelisib was administered on intermittent dosing to mitigate immune-related adverse events and infections that have been reported with oral PI3Kδ inhibitors administered daily continuously. Eligible patients with measurable disease and progression after at least two prior therapies were administered zandelisib until disease progression or intolerability. The primary efficacy endpoint was objective response rate (ORR) and the key secondary efficacy endpoint was duration of response (DOR). We report on 121 patients with FL administered zandelisib on intermittent dosing after 8 weeks of daily dosing for tumor debulking. The median number of prior therapies was 3 (range, 2-8) and 45% of patients had refractory disease. The ORR was 73% (95% confidence interval [CI], 63.9-80.4), the complete response (CR) rate was 38% (95% CI, 29.3-47.3), and the median DOR was 16.4 months (95% CI, 9.5-not reached). With a median follow-up of 14.3 months (range, 1-30.5), the median progression-free survival was 11.6 months (95% CI, 8.3-not reached). Twenty-one patients (17%) discontinued therapy due to an adverse event. Grade 3-4 class-related toxicities included 6% diarrhea, 5% lung infections, 3% colitis (confirmed by biopsy or imaging), 3% rash, 2% AST elevation, and 1% non-infectious pneumonitis. Zandelisib achieved a high rate of durable responses in heavily pretreated patients with relapsed/refractory FL. The intermittent dosing resulted in a relatively low incidence of severe class-related toxicities, which supports the evaluation of zandelisib as a single agent and in combination with indolent B-cell malignancies.

Cancer is a complex and multifaceted group of diseases with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. Dysregulation of normal signalling pathways in cancer contributes to the different hallmarks of this disease. The signalling pathway of which phosphatidylinositol 3-kinase (PI3K) is a part is not an exception. In fact, dysregulated activation of PI3K signalling pathways can result in unbridled cellular proliferation and enhanced cell survival, thereby fostering the onset and advancement of cancer. Therefore, there is substantial interest in developing targeted therapies specifically aimed at inhibiting the PI3K enzyme and its associated pathways. Also, the therapeutic interest on pyrazoles and indazoles has been growing due to their various medicinal properties, namely, anticancer activity. Derivatives of these compounds have been studied as PI3K inhibitors, and they showed promising results. There are already some PI3K inhibitors approved by Food and Drug Administration (FDA), such as Idelalisib (Zydelig®) and Alpelisib (Piqray®). In this context, this review aims to address the importance of PI3K in cellular processes and its role in cancer. Additionally, it aims to report a comprehensive literature review of PI3K inhibitors, containing the pyrazole and indazole scaffolds, published in the last fifteen years, focusing on structure-activity relationship aspects, thus providing important insights for the design of novel and more effective PI3K inhibitors.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma subtype, accounting for 15-20% of all lymphoma diagnoses. Although typically slow-growing and responsive to frontline therapies, advanced-stage FL remains incurable with current treatments and typically follows a chronic relapsing/remitting course with increasingly shorter responses to subsequent lines of therapy. Outcomes are highly variable; some patients experience prolonged first remissions that may approximate a 'functional cure'. By contrast, a significant minority of patients experience disease progression shortly after frontline treatment resulting in high rates of lymphoma-related mortality. Reflecting on the heterogeneous natural history of FL, clinical practice varies widely, particularly in controversial areas, including appropriate disease staging, selection of management strategies and duration of clinical follow-up. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice.

MIL62, a novel glycoengineered type Ⅱ anti-CD20 monoclonal antibody, with a nearly completely afucosylated N-glycans in Fc region, has demonstrated superior activity compared with rituximab and obinutuzumab in vitro and in vivo, respectively.

This multicentre, single-arm, phase 1b/2 trial aimed to explore the efficacy, pharmacokinetics, and safety of MIL62 combined with lenalidomide in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or marginal zone lymphoma (MZL). Eligible patients included those who had histopathologically confirmed CD20 positive FL (grade 1-3a) or MZL and failed to be treated with rituximab. Patients received intravenously infused MIL62 1000 mg (cycle 1: day 1, 15; cycles 2-8: day 1, cycles 10 and 12: day 1) combined with oral lenalidomide (once a day, days 2-22, the initial dose was 10 mg, and the maximum dose was 20 mg) for 12 cycles, 28 days as a cycle. The primary endpoint was objective response rate (ORR) assessed by investigator per Lugano 2014 criteria every 3 cycles. This study was registered in ClinicalTrials.gov (NCT04110301).

Between November 22, 2019 and December 22, 2020, 54 patients were enrolled from 11 hospitals in China and received study treatment. Fifty patients were included in the efficacy analysis set, and 43 patients (86%, 95% CI: 73, 94) achieved objective response, meeting the pre-specified primary endpoint. Disease control rate was 96% (48/50, 95% CI: 86, 100), proportion of patients with duration of response (DoR) > 6 months was 77% (33/43). The median follow-up for survival was 12.3 months (IQR 12.0-12.6). The 1-year progression-free survival rate was 72% (95% CI: 57, 83), 9-month DoR rate was 74% (95% CI: 58, 85), and 1-year overall survival rate was 98% (95% CI: 85, 100). Most common TRAEs were neutropenia (93%, 50/54), leukopenia (85% 46/54), thrombocytopenia (61% 33/54), lymphopenia (32% 17/54), and alanine aminotransferase increased (20% 11/54).

MIL62 combined with lenalidomide showed promising efficacy in patients with R/R FL and MZL. A multicentre, randomized, open-label, phase Ⅲ trial of MIL62 combined with lenalidomide versus lenalidomide in anti-CD20 monoclonal antibody refractory FL patients is ongoing (NCT04834024).

Beijing Mabworks Biotech Co. Ltd, Beijing China and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

Parsaclisib, a potent and highly selective phosphoinositide 3-kinase δ inhibitor, has shown clinical activity in relapsed/refractory (R/R) B-cell lymphoma. The phase 1 CITADEL-112 (NCT03424122) study assessed safety and efficacy of parsaclisib in combination with investigator choice standard of care (SOC; rituximab [Treatment A], rituximab plus bendamustine [Treatment B], or ibrutinib [Treatment C]) in 50 patients with R/R B-cell lymphoma. The most common treatment-emergent adverse events included neutropenia (62.5%, 50.0%, and 50.0% of patients in Treatments A, B, and C, respectively); diarrhea (37.5%) and anemia (31.3%) in Treatment A; abdominal pain, asthenia, diarrhea, and nausea (each 33.3%) in Treatment B; and increased alanine and aspartate aminotransferase (each 37.5%) in Treatment C. Objective responses were observed in 13 patients (81.3%) in Treatment A, 10 (55.6%) in Treatment B, and 8 (50.0%) in Treatment C. Parsaclisib combined with SOC therapies had an expected safety profile and promising efficacy in patients with R/R B-cell lymphomas.

PI3Kδ is expressed predominately in leukocytes and is commonly found to be aberrantly activated in human B-cell lymphomas. Although PI3Kδ has been intensively targeted for discovering anti-lymphoma drugs, the application of currently approved PI3Kδ inhibitors has been limited due to unwanted systemic toxicities, thus warranting the development of novel PI3Kδ inhibitors with new scaffolds.

We designed TYM-3-98, an indazole derivative, and evaluated its selectivity for all four PI3K isoforms, as well as its efficacy against various B-cell lymphomas both in vitro and in vivo.

We identified TYM-3-98 as a highly selective PI3Kδ inhibitor over other PI3K isoforms at both molecular and cellular levels. It showed superior antiproliferative activity in several B-lymphoma cell lines compared with the approved first-generation PI3Kδ inhibitor idelalisib. TYM-3-98 demonstrated a concentration-dependent PI3K/AKT/mTOR signaling blockage followed by apoptosis induction. In vivo, TYM-3-98 showed good pharmaceutical properties and remarkably reduced tumor growth in a human lymphoma xenograft model and a mouse lymphoma model.

Our findings establish TYM-3-98 as a promising PI3Kδ inhibitor for the treatment of B-cell lymphoma.

Launched in 1992, the FDA accelerated approval program grants drugs indicated in rare/life threatening diseases the ability to be marketed at a faster pace than through the traditional track. Each manufacturing company presents its drug to the FDA, and within 60 days it will determine if the drug is eligible for this path. Many drugs that were initially approved through this route, subsequently did not demonstrate their clinical benefits. With cancer being a leading cause of death, a vast majority of drugs that have been approved/withdrawn from this pathway are indicated within oncology. There are a wide variety of cancer subtypes and therapeutic target sites that these drugs have been evaluated for. Herein, is an overview of the 17 oncology drugs, spanning 22 cancer-related indications, that had been approved within the accelerated route and subsequently withdrawn.