A Case of Anaplastic Large Cell Lymphoma (ALCL) after Immune Check Point Inhibitor (ICI) Therapy
Introduction/Background/Significance: Therapeutic PD-1/PDL-1 (Programmed Death Ligand) inhibition is associated with hyper-progression of certain T-cell malignancies. PD-1 receptor is a known potent tumor suppressor in T-cell lymphoma mouse models. We report a case of ALK (Anaplastic Lymphoma Kinase) negative ALCL diagnosis in a patient with lung cancer during treatment with Pembrolizumab (PD-1 inhibitor). Our case suggests a potential association between ICI, and ALCL development and highlights caution in trials targeting immunosuppressive microenvironment with PD-1 inhibition combined with T-cell therapy.
Materials and Methods/Case Presentation/Objective: 64- year-old female with stage IIB adenocarcinoma (PDL-1 positive, EGFR,/ALK negative) of the lung underwent right upper lobe resection, lymphadenectomy and adjuvant platinum-based chemotherapy with pembrolizumab and was in complete remission (CR). She continued on pembrolizumab maintenance (8th cycle) when she presented with gum soreness, fatigue, and neck swelling. Physical exam revealed an alveolar/mandibular mass that was biopsied, and imaging studies were obtained. PET imaging identified several hypermetabolic lymphadenopathy, hepatic lesions and extensive bony disease. Histological assessment showed ALCL, CD20 negative, CD3+, CD5+, CD30+, CD56-,ALK negative and PD-1/ PDL-1 negative. FISH for DUSP22 rearrangement was negative, and atypical signal pattern with TBL1XR1/Tp63 probe indicated Tp63gene del/3q26 del. PCR for T-cell gene rearrangement was positive (TCR: gamma V2-5, 8-11). Sequencing studies in blood detected high tumor fraction with MGMT promoter methylation, Tp53 P151S, variants of clonal hematopoiesis in TET2, alterations in CIC, IRS2, NCOR1, PIK3R3, PRDM1, PRKAR1A and RICTOR. Patient was diagnosed with stage IV ALCL and pembrolizumab was discontinued. Treatment with Brentuximab-Vedotin (BV), cyclophosphamide, vincristine, and prednisone (BV/CHP) was initiated with symptomatic improvement. She had a CR in PET imaging after 6 cycles, declined stem cell transplant and continued with BV.
Results/Description/Main Outcome Measures: Prognosis of ALK negative ALCL is poor and TP63 rearranged ALCLs have worse outcome. Amplification of the PRKCQ gene in malignant cells (T cell activation/NF-κB pathway) in peripheral T-cell lymphoma (PTCL) and genes related to tumor-associated T-regs (MAGEH1, CTLA4, CD27, CD70, TNFRSF4, and LAG-3) in adult T-cell leukemia/lymphoma (ATLL) were associated with few cases of hyper-progression after ICI in clinical trials. In our case, PD-1/PD-L1 blockade with ICI resulted in the expansion of gamma-receptor rearranged T-cell clones. PD-1 is known to negatively regulate PI3K/AKT and NF-κB signaling pathways inhibiting malignant T-cell growth. Mutations in oncogenes (PIK3R3 Y195C, RICTOR G1572E), tumor suppressor genes (Tp53) and epigenetic alterations affecting transcription (NCOR1, MGMT promoter methylation) detected in sequencing studies likely contributed to development of ALCL in our case.
Conclusions: Molecular interactions involving TCR, PD-1 receptor and PDL-1 prevent deregulated T- cell proliferation and activation after an immune response. PD-1/PDL-1 blockade can result in rapid expansion of exhausted T-cell phenotype as noted in T-cell leukemia studies. We present the first case of ALK-negative ALCL associated with ICI. Further research is needed to understand the interaction between T- cell and the PD-1/PDL-1 axis with ICI treatment.
References
Ohmoto A, Fuji S. Rapid T-cell lymphoma progression associated with immune checkpoint inhibitors. Expert Rev Hematol. 2023 Jul-Dec;16(7):535-541.
Gao Y, Hu S, Li R, et al.. Hyperprogression of cutaneous T cell lymphoma after anti-PD-1 treatment. JCI Insight. 2023 Feb 22;8(4):e164793.
