PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma

Nayak, Lakshmi; Iwamoto, Fábio M.; LaCasce, Ann S.; Mukundan, Srinivasan; Roemer, Margaretha G.M.; Chapuy, Bjoern; Armand, Philippe; Rodig, Scott J.; Shipp, Margaret A.

doi:10.1182/blood-2017-01-764209

Cited by 395 publications

(248 citation statements)

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“…9,11,12 Recently, a study 13 found that all 5 patients with relapsed or refractory primary central nervous system large B-cell lymphoma or testicular large B-cell lymphoma treated with PD-1 blockade experienced an objective response, and 60% remained progression free at 13 to 17 months. Taken together, in certain lymphomas, chromosome 9p24.1 alterations, which include PDL1, are relatively common and are associated with high susceptibility to PD-1 blockade.…”

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confidence: 99%

Prevalence ofPDL1Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors

et al. 2018

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IMPORTANCE Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors. OBJECTIVES To examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors. DESIGN, SETTING, AND PARTICIPANTS This retrospective study (October 1, 2012, to October 1, 2017) used a deidentified tumor database from a commercial company and annotated clinical records from a subset of patients treated at a university tertiary referral center. The study analyzed 118 187 tumors from the deidentified database, including a clinically annotated subgroup of 2039 malignant tumors. INTERVENTIONS Comprehensive genomic profiling was performed on all samples to determine PDL1 amplification, microsatellite instability, and tumor mutational burden (TMB). A subset of patients was treated with PD-1/PD-L1 blockade. MAIN OUTCOMES AND MEASURES The prevalence of PDL1 amplification was determined among 118 187 patient samples that underwent next-generation sequencing. Solid tumors treated with checkpoint blockade were evaluated for response and progression-free survival (PFS). RESULTS Of the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors. Most PDL1-amplified tumors (84.8%) had a low to intermediate TMB. PDL1 amplification did not always correlate with high-positive PD-L1 expression by immunohistochemical analysis. Six of 9 patients (66.7%) from 1 center with PDL1-amplified solid tumors had objective responses after checkpoint blockade administration. The median PFS among all treated patients was 15.2 months. Responders included 1 patient with glioblastoma (PFS, ≥5.2 months), 2 patients with head and neck squamous cell cancer (PFS, ≥9 and 15.2 months), 2 patients with metastatic basal cell cancer (PFS, 3.8 and ≥24.1 months), and 1 patient with urothelial cancer (PFS, ≥17.8 months). CONCLUSIONS AND RELEVANCE The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors. Additional large-scale, prospective studies of PDL1-amplified cancers are warranted to confirm the responses to checkpoint blockade described herein, even in the absence of microsatellite instability, high PD-L1 expression, and a high TMB.

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Prevalence ofPDL1Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors

et al. 2018

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“…In patients with relapsed or refractory PMBCL including patients who were treated after autoHCT failure, Pembrolizumab was associated with a promising ORR that was durable for several months, although the study is still ongoing (50). Similarly, in smaller case series, anti-PD-1 inhibitors have demonstrated high efficacy in patients with Richter’s transformation of chronic lymphocytic leukemia (CLL) (51), relapsed NK/T cell lymphomas (52), relapsed/refractory primary CNS lymphoma (PCNSL) (53), or mediastinal gray zone lymphoma(54)…”

Section: Checkpoint Inhibition and Autohct (Table 1)mentioning

confidence: 99%

Stop and go: hematopoietic cell transplantation in the era of chimeric antigen receptor T cells and checkpoint inhibitors

Ghosh

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Perales

2017

Current Opinion in Oncology

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Purpose of review For several decades, hematopoietic cell transplantation has been considered the standard curative therapy for many patients with hematological malignancies. In addition to the cytotoxic effects of the chemotherapy and radiation used in the conditioning regimen, the benefits of hematopoietic cell transplantation are derived from a reset of the immune system and harnessing the ability of donor T cells to eliminate malignant cells. With the dawn of the era of immunotherapies in the form of checkpoint inhibitors and chimeric antigen receptor T cells, the role of hematopoietic cell transplantation has evolved. Recent findings Immunotherapy with checkpoint inhibitors is increasingly being used for relapsed Hodgkin and non-Hodgkin lymphoma after autoHCT. Checkpoint inhibitors are also being tested after alloHCT with observable benefits in treating hematological malignancies, but with a potential risk of increased GVHD and transplant-related mortality. Immunotherapy with CD19 CAR T cells are powerful options with aggressive B cell malignancies both for therapy and as induction leading to alloHCT. Summary While immunotherapies with checkpoint inhibition and CAR T cells are increasing being used to treat hematological malignancies, HCT remains a standard of care for most of the diseases with the best chance of cure. Combination of these therapies with HCT has the potential to more effectively treat hematological malignancies.

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“…Importantly, the disease tends to relapse at extranodal sites, frequently the CNS [51]. Recent genomic analyses have shown that PCNSL and PTL share molecular features: On the one hand, mutations in MYD88, CD79B and CARD11 (as in ABC lymphoma) are frequently found [52] and, on the other hand, copy number alterations of 9p24.1 with the associated increased expression of PD-L1 and PD-L2 have been described in a high proportion of patients, providing the rationale to treat patients with CIs within clinical trials [53][54][55]. Initially, there have been anecdotal responses, and recently [56], a series of 5 patients (4 PCNSL, 1 PTL) has been reported.…”

Section: Primary Central Nervous System Lymphoma and Primary Testiculmentioning

confidence: 99%

Checkpoint Inhibition in Non-Hodgkin's Lymphoma

Heß

2017

Oncol Res Treat

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As patients continue to die from malignant lymphoma, novel treatment options continue to be warranted. To successfully grow and spread, tumor cells need to escape the immune system; therefore, the augmentation or restoration of immune effectors against the malignant cell could be of great value, as shown, e.g., for allogeneic transplantation. A deepened understanding of the regulation of activation and inhibition of the T cell-based effector mechanisms has led to the development of drugs that are able to modify specific checkpoints of this system and thereby raise an immune response against tumor cells. With dramatic responses observed in Hodgkin's disease (HD), interest has risen to explore these drugs in non-Hodgkin's lymphoma (NHL). Available data underline the potential of checkpoint inhibitors in a variety of lymphoma entities, such as primary mediastinal B cell lymphoma (PMBCL) or central nervous system (CNS) lymphoma, and there is hope that a significant proportion of patients will finally benefit. However, intensive efforts are needed to develop optimal screening tools, combinations, and sequences to explore the full potential of these new classes of therapeutic agents.

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PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma

Abstract: Key Points Genetic analysis reveals frequent 9p24.1/PD-L1/PD-L2 copy-number alterations and increased expression of the PD-1 ligands in PCNSL and PTL. PD-1 blockade with nivolumab demonstrated activity in patients with relapsed/refractory PCNSL and PTL.

Cited by 395 publications

References 23 publications

Prevalence ofPDL1Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors

Prevalence ofPDL1Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors

Stop and go: hematopoietic cell transplantation in the era of chimeric antigen receptor T cells and checkpoint inhibitors

Checkpoint Inhibition in Non-Hodgkin's Lymphoma

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