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Case Reports
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Figure 2. Identification and quantifica- tion of TP53 I195S mutation. (A) The raw mutation calls visualized in Integrated Genome Viewer (IGV, Broad Institute, Cambridge, MA) are shown for the pretreatment (top) and post- treatment (bottom) blood samples. The T584G DNA mutation that corresponds to the protein change I195S was pres- ent in 78% of the reads in the pretreat- ment sample but absent in the post- treatment sample. (B) Variant allele frequency of missense, nonsense, and frameshift mutations identified in the metastatic melanoma biopsy. The TP53 I195S mutation identified in the blood is highlighted in red. (C) Diagnostic bone marrow biopsy speci- men stained with B-cell marker BSAP (red) and PD-L1 (brown).
and well-tolerated. Our data do suggest that studying PD-1 blockade in earlier lines of therapy for relapsed or refractory disease, particularly prior to utilizing chemotherapy, may be more likely to affect a therapeutic response due to the potential to harness a more intact immune system.
In this patient, the SMZL population expressed PD-L1, suggesting a direct T-cell mediated effect of pem- brolizumab. The role of the tumor microenvironment in response to PD-1 blockade remains an area of active study, and despite the relative paucity of publications looking at checkpoint blockade in MZL, there does seem to be significant biological variability between and within different types of MZL.14,15 For example, in one study of 54 SMZL, PD-L1 positive histiocytes and dendritic cells were found in 75% of the tumors but the Pax-5 tumor cells themselves were uniformly PD-L1 negative.16 However, in clinical studies of patients with NHL, expression of PD-L1 does not always predict response to PD-1 blockade.12,13 These observations further raise the potential role of the tumor microenvironment in media- ting the response to these and other immunotherapies. Our findings and these data provide biological rationale
for the use of PD-1 blockade in this setting.
TP53 missense mutations are common in B-NHL, including at the known hotspots R175H and R248Q. The TP53 I195S missense mutation identified in this case occurs in the DNA binding domain of TP53 where most of the hotspot mutations occur.17 In a prior publication from our group we showed that mutations at position I195 generally, and I195S specifically, confer dominant negative activity on P53.18 In one study that extracted SMZL cases from 14 different studies, TP53 was the third most commonly mutated gene and present in 15% of cases.19 While the identification of a TP53 mutations does not provide diagnostic information, TP53 mutations in SMZL are associated with a worse prognosis and overall survival, further highlighting the dramatic response in
this patient.20
Taken together, this case report highlights the potential
for PD-1 directed therapy in the frontline setting for mar- ginal zone lymphoma, the potential value of molecular analysis in identifying residual disease after treatment, and the importance of considering hematopoietic muta- tions when interpreting solid tumor sequencing data. We believe that a prospective study of PD-1 blockade early in
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