PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma.
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ABSTRACT:
SUBMITTER: Nayak L
PROVIDER: S-EPMC5766844 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).
| S-EPMC4348009 | biostudies-literature
Project description:Primary central nervous system lymphoma is an invasive malignant lymphoma confined to the central nervous system. Although patients undergoing first-line treatment can achieve complete response, most of them still relapse within two years. Relapsed lymphoma is derived from occult lymphoma cells, and B cell receptor pathway activation and immune escape are the key mechanisms for the pathogenesis of PCNSL. Most relapses are in the central nervous system, a small number of relapses are isolated systemic relapses, and clinical symptoms occur early and vary. Current treatments for relapse include high-dose methotrexate rechallenge and other regimens of chemotherapy, whole-brain radiation therapy, hematopoietic stem-cell transplantation, targeted therapy and immunotherapy, which have become promising treatments. The overall prognosis of relapsed PCNSL is very poor, although it is affected by many factors. This article summarizes the mechanisms, related factors, clinical features, follow-up, treatment and prognosis of relapsed primary central nervous system lymphoma.
| S-EPMC8118624 | biostudies-literature
Project description:BACKGROUND: Lenalidomide is an immunomodulator agent that exhibits efficacy in multiple myeloma and haematological malignancies including refractory/relapsed diffuse large B-cell (DLBC) systemic lymphoma. METHODS: Retrospective review of PCNSL patients treated with lenalidomide at the Pitié-Salpêtrière hospital. Inclusion criteria were: 1) immunocompetent status 2) pathologically proven diagnosis of DLBC-PCNSL, 3) recurrent or refractory disease after at least two prior chemotherapy treatments, including intravenous high-dose methotrexate and cytarabine based regimens, 4) lenalidomide administered orally, at a dose of 25 mg/day on days 1-21 of a 28-days cycle. MRI scans were performed monthly. Response was evaluated according to the IPCG criteria. RESULTS: Between June 2011 and March 2013, 6 patients (4 women and 2 men) met the inclusion criteria. Lenalidomide was given as 3rd line in four patients, as 4th line in one and 5th line in one. Median age was 73.5 years (range 64-78) and median Karnofsky Performance Status was 60 (range 40-70). Two patients achieved complete response (CR). Patient 1 received a total of 9 monthly cycles of lenalidomide without any steroids and is still in remission after a follow-up of 18 months from the start of the treatment. Patient 2 achieved a CR and was off-steroids at the time of CR, but relapsed during the 3rd cycle and died after 14 weeks. Patient 3 achieved a partial response after one cycle but died suddenly during the 2nd cycle. Patients 4, 5 and 6 progressed and died 2, 5 and 6 months respectively after the start of lenalidomide. One of them who suffered from an oculo-cerebral relapse demonstrated a partial ocular response while progressing in the brain. Apart from the sudden death of unknown cause, the treatment was well tolerated. None of the patients experienced any grade III or IV toxicity. CONCLUSIONS: These results suggest that lenalidomide exhibits activity in heavily pre-treated PCNSL and is well tolerated in elderly patients. Lenalidomide efficacy on PCNSL needs to be evaluated prospectively, alone or in association with other cytotoxic agents. A phase II trial combining rituximab and lenalidomide for recurrent PCNSL is on-going in France (NCT01956695).
| S-EPMC4185581 | biostudies-literature
Project description:BackgroundRelapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL) is an intractable situation without sound treatment. Bruton's tyrosine kinase (BTK) represents an attractive drug target in PCNSL. Orelabrutinib is a new-generation BTK inhibitor with high cerebrospinal fluid (CSF) concentration. This study aimed to evaluate the efficacy and safety of orelabrutinib-containing combination therapy in patients with r/r PCNSL.MethodsWe retrospectively analyzed r/r PCNSL patients who received combination therapy with rituximab, high-dose methotrexate, temozolomide, orelabrutinib and lenalidomide, and further explored the relationship between the efficacy and genetic characteristics.ResultsA total of fifteen patients were included in this retrospective study. The overall response rate (ORR) was 86.7%, the complete remission (CR) rate was 73.3% and the disease control rate (DCR) was 93.3%. Among 13 responders, 9 patients are still receiving oral orelabrutinib and lenalidomide. The most common adverse event (AEs) was transaminase increase (66.7%). No grade 4 AE or drug-related death was reported. Genomic sequencing showed that patients who responded to orelabrutinib had abnormal NF-κB activation, while those who had no response were mainly enriched with transcriptional misregulation. Patients who had mutations in TLR, BCR, or NF-κB pathway achieved complete or partial response to the orelabrutinib-containing therapy. Moreover, the blood and cerebrospinal fluid circulating tumor DNA (ctDNA) were closely associated with tumor recurrence and treatment response and sustained tumor responses correlated with the clearance of ctDNA.ConclusionOrelabrutinib-containing regimen was effective and well-tolerated in patients with r/r PCNSL. Genome sequencing of tumor samples could help to screen patients who may respond to the orelabrutinib-containing regimen, and liquid biopsy may contribute to tracing tumor burden and monitoring treatment response.
| S-EPMC9243261 | biostudies-literature
Project description:BackgroundThe safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton's tyrosine kinase inhibitor were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL).MethodsPatients with relapsed/refractory PCNSL, Karnofsky performance status ?70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (QD) in phase 1 to evaluate dose-limiting toxicity (DLT) within 28 days using a 3+3 dose escalation design and with 480 mg QD under fasted conditions in phase 2.ResultsForty-four patients were enrolled; 20, seven and 17 received tirabrutinib at 320, 480 and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ?3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg QD had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee-assessed overall response rate (ORR) was 64%: 60% with five complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with four CR/CRu at 480 mg, and 53% with six CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1 and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild-types.ConclusionThese data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL.
| S-EPMC7850159 | biostudies-literature
Project description:Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma (NHL) confined to the brain, leptomeninges, eyes, or spinal cord. The majority of PCNSL cases occur in the immunocompetent host, the focus of this review. The prognosis of PCNSL is inferior to that of other NHL subtypes including other organ-specific subtypes of extranodal NHL. The 5- and 10-year survival proportions for PCNSL are 29.3% and 21.6%, respectively. The diagnosis and management of PCNSL differs from that of other primary brain cancers and NHL in other parts of the body.
| S-EPMC6142465 | biostudies-literature
Project description:Primary central nervous system lymphoma (PCNSL) is a rare extranodal lymphomatous malignancy that affects the brain, spinal cord, leptomeninges, or vitreoretinal space, without evidence of systemic involvement. The diagnosis of PCNSL requires a high level of suspicion because clinical presentation varies depending upon involved structures. Initiation of treatment is time sensitive for optimal neurologic recovery and disease control. In general, the prognosis of PCNSL has improved significantly over the past few decades, largely as a result of the introduction and widespread use of high-dose methotrexate (MTX) chemotherapy, which is considered the backbone of first-line polychemotherapy treatment. Upon completion of MTX-based treatment, a consolidation strategy is often required to prolong duration of response. Consolidation can consist of radiation, maintenance therapy, nonmyeloablative chemotherapy, or myeloablative treatment followed by autologous stem cell transplant. Unfortunately, even with consolidation, relapse is common, and 5-year survival rates stand at only 30% to 40%. Novel insights into the pathophysiology of PCNSL have identified key mechanisms in tumor pathogenesis, including activation of the B-cell receptor pathway, immune evasion, and a suppressed tumor immune microenvironment. These insights have led to the identification of novel small molecules targeting these aberrant pathways. The Bruton tyrosine kinase inhibitor ibrutinib and immunomodulatory drugs (lenalidomide or pomalidomide) have shown promising clinical response rates for relapsed/refractory PCNSL and are increasingly used for the treatment of recurrent disease. This review provides a discussion of the clinical presentation of PCNSL, the approach to work-up and staging, and an overview of recent advancements in the understanding of the pathophysiology and current treatment strategies for immunocompetent patients.
| S-EPMC9437714 | biostudies-literature
Project description:Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma (NHL), confined to the brain, eyes, spinal cord or leptomeninges without systemic involvement. Overall prognosis, diagnosis and management of PCNSL differ from other types of NHL. Prompt diagnosis and initiation of treatment are vital to improving clinical outcomes. PCNSL is responsive to radiation therapy, however whole-brain radiotherapy (WBRT) inadequately controls the disease when used alone and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High-dose methotrexate (HD-MTX)-based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced-dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined, however HD-MTX-based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials address the role of rituximab, and of consolidative treatment using ASCT or reduced-dose WBRT. Despite high tumor response rates to initial treatment, many patients have relapsing disease with very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on age, previous treatment and response, performance status and comorbidities at the time of relapse. Novel therapeutics targeting underlying tumor biology include small molecule inhibitors of B-cell receptor, cereblon, and mammalian target of rapamycin signaling, and immunotherapy programmed cell death 1 receptor inhibitors and chimeric antigen receptor T cells.
| S-EPMC6174646 | biostudies-literature
Project description:Primary Central Nervous System Lymphoma (PCNSL) is a rare variant of Non-Hodgkin Lymphoma (NHL) representing 1-2% of all NHL cases. PCNSL is defined as a lymphoma that occurs in the brain, spinal cord, leptomeninges, or eyes. Efforts to treat PCNSL by traditional chemotherapy and radiotherapy have generally been unsuccessful as a significant proportion of patients have frequent relapses or are refractory to treatment. The prognosis of patients with Refractory or Relapsed (R/R) PCNSL is abysmal. The optimal treatment for R/R PCNSL is poorly defined as there are only a limited number of studies in this setting. Several studies have recently shown that ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has promising results in the treatment of R/R PCNSL. However, these are preliminary studies with a limited sample size. In this systematic review, we explored and critically appraised the evidence about the efficacy of the novel agent ibrutinib in treating R/R PCNSL.
| S-EPMC8788490 | biostudies-literature
Project description: Not available
| S-EPMC8751801 | biostudies-literature