pci-32765 and Central-Nervous-System-Neoplasms

The standard regimen for the treatment of newly diagnosed primary CNS lymphoma (PCNSL) remains regimens that contain high-dose methotrexate (MTX). While these regimens can provide control for some patients, there is a dearth of options for the treatment of patients with PCNSL who cannot tolerate MTX-containing regimens, or whose cancers are refractory to MTX. In this article, we review a promising new option; ibrutinib, a Bruton tyrosine kinase inhibitor, for patients with relapsed and refractory PCNSL.

Topics: Adenine; Central Nervous System Neoplasms; Humans; Lymphoma, Large B-Cell, Diffuse; Piperidines; Prognosis

Novel insights into the pathophysiology of primary central nervous system lymphoma (PCNSL) have identified the B-cell receptor and Toll-like receptor pathway as well as immune evasion and suppressed tumor immune microenvironment as a key mechanism in the pathogenesis of PCNSL. Small molecules and novel agents targeting these aberrant pathways have been introduced into clinical trials targeting the recurrent or refractory PCNSL patient population. Agents like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs (IMiDs) like pomalidomide and lenalidomide have shown promising high response rates in the salvage setting. Here, we give an overview about the recent, exciting developments in PCNSL and summarize the results of clinical trials using novel agents in the recurrent and refractory salvage setting, which include immune checkpoint inhibitors, IMiDs, as well as BTK, phosphatidylinositol-3 kinase, and mammalian target of rapamycin inhibitors.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aminopyridines; Antineoplastic Agents, Immunological; Burkitt Lymphoma; Central Nervous System Neoplasms; Humans; Immunologic Factors; Lenalidomide; Lymphoma, Large B-Cell, Diffuse; Lymphoma, T-Cell; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rituximab; Salvage Therapy; Thalidomide; Toll-Like Receptors; TOR Serine-Threonine Kinases; Tumor Escape

Primary central nervous system lymphoma (PCNSL) is a rare aggressive extranodal non- Hodgkin lymphoma. Although high remission rates can be achieved with high-dose methotrexate-based immunochemotherapy, risk of relapse and associated death is still substantial in at least a third of patients. Novel agents for treating lymphoid malignancies have substantially enriched treatment options for PCNSL. We herein systematically review the existing clinical evidence of novel agents in treatment of PCNSL, summarize ongoing studies, and discuss perspectives. The body of evidence for novel agents is still limited to noncomparative studies, but the most promising approaches include Bruton kinase inhibition with ibrutinib and immunomodulatory treatment (eg, with lenalidomide). Targeting the mammalian target of rapamycin pathway does not seem to have a meaningful clinical benefit, and evidence of checkpoint inhibition with nivolumab is limited to anecdotal evidence. Future studies should embrace the concept of induction and maintenance therapy as well as the combination of drugs with different mechanisms of action. Selection of patients based on molecular profiling and relapse patterns should be another aspect informing future comparative trials, which are urgently needed to improve prognosis for patients with PCNSL.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Humans; Lenalidomide; Lymphoma, Non-Hodgkin; Nivolumab; Piperidines; Pyrazoles; Pyrimidines; Recurrence

Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Central Nervous System Neoplasms; Disease-Free Survival; Female; Follow-Up Studies; Humans; Lymphoma; Male; Middle Aged; Piperidines; Survival Rate

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Circulating Tumor DNA; Female; Humans; Lymphoma; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rituximab; Treatment Outcome; Young Adult

Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal centre B-cell subtype, with unmet medical needs. This study aimed to evaluate the efficacy and toxicity of ibrutinib in DLBCL-PCNSL PATIENTS AND METHODS: This prospective, multicentre, phase II study involved patients with relapse or refractory(R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma. The treatment consisted of ibrutinib (560 mg/day) until disease progression or unacceptable toxicity occurred. The primary outcome was the disease control (DC) rate after two months of treatment (P0 < 10%; P1 > 30%).. Fifty-two patients were recruited. Forty-four patients were evaluable for response. After 2 months of treatment, the DC was 70% in evaluable patients and 62% in the intent-to-treat analysis, including 10 complete responses (19%), 17 partial responses (33%) and 5 stable diseases (10%). With a median follow-up of 25.7 months (range, 0.7-30.5), the median progression-free and overall survivals were 4.8 months (95% confidence interval [CI]; 2.8-12.7) and 19.2 months (95% CI; 7.2-NR), respectively. Thirteen patients received ibrutinib for more than 12 months. Two patients experienced pulmonary aspergillosis with a favourable (n = 1) or fatal outcome (n = 1). Ibrutinib was detectable in the cerebrospinal fluid (CSF). The clinical response to ibrutinib seemed independent of the gene mutations in the BCR pathway.. Ibrutinib showed clinical activity in the brain, the CSF and the intraocular compartment and was tolerated in R/R PCNSL. The addition of ibrutinib to standard methotrexate-base induction chemotherapy will be further evaluated in the first-line treatment.. NCT02542514.

Topics: Adenine; Aged; Aged, 80 and over; Central Nervous System Neoplasms; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Lymphoma; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Prognosis; Prospective Studies; Pyrazoles; Pyrimidines; Retinal Neoplasms; Salvage Therapy; Survival Rate

Relapsed/refractory (r/r) central nervous system lymphoma (CNSL) exhibits aggressive behavior and poor outcomes. As an effective bruton tyrosine kinase (BTK) inhibitor, ibrutinib yields benefits in B-cell malignancies.. We aimed to explore the efficacy of ibrutinib in treating r/r CNSL patients, and whether genomic variants impact treatment outcomes.. The ibrutinib-based regimens in 12 r/r primary CNSL (PCNSL) and 2 secondary CNSL (SCNSL) patients were analyzed retrospectively. The impact of genetic variants on the effects of treatments was examined using whole-exome sequencing (WES) technology.. In PCNSL, the overall response rate was 75%, with median overall survival (OS) not reached (NR) and progression-free survival (PFS) of 4 months. Both SCNSL patients responded to ibrutinib, with median OS NR and PFS of 0.5-1.5 months. Infections were common during ibrutinib therapy (42.86%). The PCNSL patients harboring gene mutations in PIM1, MYD88 and CD79B, and the proximal BCR and nuclear factor kappa B (NF-κB) pathways responded to ibrutinib. Patients who harbored simple genetic variants and those with a low tumor mutation burden (TMB; 2.39-5.56/Mb) responded swiftly and maintained remission for more than 10 months. A patient with a TMB of 11/Mb responded to ibrutinib but continued to experience disease progression. In contrast, patients with complex genomic features, especially extremely high TMB (58.39/Mb), responded poorly to ibrutinib.. Our study demonstrates that ibrutinib-based therapy is effective and relatively safe for the treatment of r/r CNSL. Patients with less genomic complexity, especially with regard to TMB, might benefit more from ibrutinib regimens.

Topics: Central Nervous System; Central Nervous System Neoplasms; Genomics; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Retrospective Studies

Topics: Central Nervous System Neoplasms; Chronic Disease; Humans; Lymphoma; Neoplasm Recurrence, Local; Retinal Neoplasms; Vitreous Body

Topics: Adenine; Central Nervous System; Central Nervous System Neoplasms; Humans; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Mediastinal Neoplasms; Piperidines; Salvage Therapy

Topics: Adenine; Adult; Central Nervous System Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Transplantation, Homologous; Treatment Outcome; Young Adult

Topics: Adenine; Aged; Blood Cell Count; Central Nervous System Neoplasms; Cerebrospinal Fluid; Diagnosis, Differential; Eye Diseases; Eye Pain; Humans; Magnetic Resonance Imaging; Male; Optic Disk; Optic Nerve; Pain; Piperidines; Tomography, X-Ray Computed; Vision Disorders; Waldenstrom Macroglobulinemia

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Piperidines; Prognosis; Retrospective Studies; Survival Analysis; Temozolomide

Topics: Adenine; Administration, Oral; Central Nervous System Neoplasms; Female; Humans; Hypersensitivity, Immediate; Middle Aged; Piperidines

Topics: Adenine; Aged; Brain Diseases; Central Nervous System Neoplasms; Female; Humans; Immunotherapy; Piperidines; Syndrome

Topics: Adenine; Central Nervous System Neoplasms; Humans; Piperidines; Pyrazoles; Pyrimidines

Topics: Adenine; Aged; Aged, 80 and over; Central Nervous System Neoplasms; Female; Humans; Lymphoma; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Retrospective Studies

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Piperidines; Positron Emission Tomography Computed Tomography; Temozolomide

Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL.. Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry.. Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages.. These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Central Nervous System Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Exportin 1 Protein; Female; Humans; Hydrazines; Karyopherins; Lymphoma, Non-Hodgkin; Macrophages; Mice; Mice, Nude; Piperidines; Receptors, Cytoplasmic and Nuclear; Survival Rate; Triazoles; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Disease Progression; Female; Humans; Lymphoma; Male; Methotrexate; Middle Aged; Off-Label Use; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Retrospective Studies; Time Factors

Central nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon. Here we present the case of a 70-year-old male patient who was diagnosed with classic MCL in 2015. The patient achieved complete remission (CR) in 2017 but relapsed with CNS involvement in 2019. He entered a deep coma and was treated with ibrutinib (560 mg daily) via nasogastric tube. He regained full consciousness after 15 days, and the presence of lymphoma cells in his cerebrospinal fluid disappeared 3 months later. We believe that ibrutinib administration via nasogastric tube is effective for MCL patients with CNS relapse.

Topics: Adenine; Aged; Central Nervous System; Central Nervous System Neoplasms; Humans; Lymphoma, Mantle-Cell; Male; Neoplasm Recurrence, Local; Piperidines

Topics: Adenine; Antineoplastic Agents; Central Nervous System Neoplasms; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Treatment Outcome; Waldenstrom Macroglobulinemia

Chronic lymphocytic leukemia (CLL) is a disorder of B cells that affects humoral as well as cell-mediated immunity. Protection against cryptococcal infections is mounted by an intricate and synchronized interplay of both integral arms of immunity. Whether CLL or small molecule tyrosine kinase inhibitors are independently predisposing hosts to cryptococcal infections remain to be explored. Herein, we present a report of a patient who developed disseminated cryptococcosis while receiving ibrutinib therapy for CLL in the salvage setting. We further present relevant literature available thus far on the topic and discuss immunologic mechanisms that may be involved in the fungal pathogenesis in such patients.

Topics: Adenine; Aged, 80 and over; Central Nervous System Neoplasms; Cryptococcosis; Humans; Male; Piperidines; Pyrazoles; Pyrimidines

Primary CNS lymphomas (PCNSL) are rare and poor prognosis diffuse large B-cell lymphomas. Because of the brain tumor environment and the restricted distribution of drugs in the CNS, specific PCNSL patient-derived orthotopic xenograft (PDOX) models are needed for preclinical research to improve the prognosis of PCNSL patients. PCNSL patient specimens (n = 6) were grafted in the caudate nucleus of immunodeficient nude mice with a 83% rate of success, while subcutaneous implantation in nude mice of human PCNSL sample did not generate lymphoma, supporting the role of the brain microenvironment in the PCNSL physiopathology. PDOXs showed diffuse infiltration of B-cell lymphoma cells in the brain parenchyma. Each model had a unique mutational signature for genes in the BCR and NF-κB pathways and retained the mutational profile of the primary tumor. The models can be stored as cryopreserved biobank. Human IL-10 levels measured in the plasma of PCNSL-PDOX mice showed to be a reliable tool to monitor the tumor burden. Treatment response could be measured after a short treatment with the targeted therapy ibrutinib. In summary, we established a panel of human PCNSL-PDOX models that capture the histological and molecular characteristics of the disease and that proved suitable for preclinical experiments. Our methods of generation and characterization will enable the generation of additional PDOX-PCNSL models, essential tools for cognitive and preclinical drug discovery.

Topics: Adenine; Animals; Caudate Nucleus; Central Nervous System Neoplasms; Disease Models, Animal; Heterografts; Humans; Interleukin-10; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Nude; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Tumor Burden

Monotherapy clinical trials with mutation-targeted kinase inhibitors, despite some success in other cancers, have yet to impact glioblastoma (GBM). Besides insufficient blood-brain barrier penetration, combinations are key to overcoming obstacles such as intratumoral heterogeneity, adaptive resistance, and the epistatic nature of tumor genomics that cause mutation-targeted therapies to fail. With now hundreds of potential drugs, exploring the combination space clinically and preclinically is daunting. We are building a simulation-based approach that integrates patient-specific data with a mechanistic computational model of pan-cancer driver pathways (receptor tyrosine kinases, RAS/RAF/ERK, PI3K/AKT/mTOR, cell cycle, apoptosis, and DNA damage) to prioritize drug combinations by their simulated effects on tumor cell proliferation and death. Here we illustrate a first step, tailoring the model to 14 GBM patients from The Cancer Genome Atlas defined by an mRNA-seq transcriptome, and then simulating responses to three promiscuous FDA-approved kinase inhibitors (bosutinib, ibrutinib, and cabozantinib) with evidence for blood-brain barrier penetration. The model captures binding of the drug to primary targets and off-targets based on published affinity data and simulates responses of 100 heterogeneous tumor cells within a patient. Single drugs are marginally effective or even counterproductive. Common copy number alterations (PTEN loss, EGFR amplification, and NF1 loss) have a negligible correlation with single-drug or combination efficacy, reinforcing the importance of postgenetic approaches that account for kinase inhibitor promiscuity to match drugs to patients. Drug combinations tend to be either cytostatic or cytotoxic, but seldom both, highlighting the need for considering targeted and nontargeted therapy. Although we focus on GBM, the approach is generally applicable.

Topics: Adenine; Anilides; Aniline Compounds; Antineoplastic Agents; Apoptosis; Blood-Brain Barrier; Cell Cycle; Cell Proliferation; Central Nervous System Neoplasms; Clinical Trials as Topic; Computer Simulation; Drug Discovery; Drug Therapy, Combination; Genomics; Glioblastoma; Humans; Models, Theoretical; Nitriles; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Quinolines; RNA, Messenger; Stochastic Processes; Transcriptome

Topics: Adenine; Central Nervous System Neoplasms; Humans; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Retreatment; Salvage Therapy; Treatment Outcome

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Central Nervous System; Central Nervous System Neoplasms; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines

Topics: Adenine; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain; Central Nervous System Neoplasms; Humans; Lymphoma, Mantle-Cell; Magnetic Resonance Imaging; Male; Middle Aged; Multicenter Studies as Topic; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Recurrence; Retreatment; Treatment Outcome; United Kingdom

Topics: Adenine; Antineoplastic Agents; Biomarkers; Blood-Brain Barrier; Central Nervous System Neoplasms; Humans; Immunophenotyping; Magnetic Resonance Imaging; Male; Middle Aged; Piperidines; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed; Treatment Outcome; Waldenstrom Macroglobulinemia

Topics: Adenine; Aged; Antineoplastic Agents; Central Nervous System Neoplasms; Female; Follow-Up Studies; Humans; International Cooperation; Lymphoma; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies

The risk of central nervous system (CNS) dissemination in mantle cell lymphoma (MCL) is low and occurs late in the course of the disease. However, prognosis in such cases remains extremely poor despite high-dose antimetabolite chemotherapy. Among novel drugs used to treat relapsing MCL patients, ibrutinib, an oral inhibitor of Bruton tyrosine kinase, shows great promise. Here we report the clinical observation of 3 MCL patients with symptomatic CNS relapse treated with single-agent ibrutinib. All 3 patients had dramatic and rapid responses with almost immediate recovery from symptoms. We also confirmed that ibrutinib crosses the blood-brain barrier with parallel pharmacokinetic analyses in plasma and cerebrospinal fluid using a validated LC-MS/MS method. All responses were ongoing after 2 months to 1 year of follow-up.

Topics: Adenine; Aged; Antineoplastic Agents; Central Nervous System Neoplasms; Female; Humans; Lymphoma, Mantle-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Recurrence