Contributions
Abstract: PB2484
Type: Publication Only
Background
Cytokine release syndrome (CRS) is a severe toxicity which is associated with the elevation of inflammatory cytokines and presumably with the activation of T cells. PD-1 is one of immune checkpoint molecules expressed on activated T cells and its immune regulation is thought to be the important target for anticancer therapy. Recent studies reported that patients received allogeneic stem cell transplantation (Allo-SCT) after PD-1 blockade often developed severe CRS followed by refractory GVHD. However, the safety of the treatment sequence of PD-1 blockade and autologous stem cell transplantation (Auto-SCT) has not been reported so far.
Aims
We demonstrate a case study about severe CRS after Auto-SCT with pretreatment by Nivolumab to characterize the abnormality of lymphoid immune reaction and clinical findings after the therapeutic combination.
Methods
A 63-year-old man was diagnosed with classical Hodgkin lymphoma (HD). His disease was resistant to several lines of chemotherapies including ABVD, DHAP, IDEA (Ifosphamide, Dexamethasone Etoposide and Cytarabine) and Brentuximab Vedotin. However, the disease was progressed with the enlargement of left subclavian lymph node. He received 22 courses of Nivolumab and achieved PR again. Consequently, he received Auto-SCT with LEED. On Day 5, he became febrile to 38.5℃ and was administered anti-biotics as febrile neutropenia. On Day 6, body temperature rise of up to 40℃, erythema of the whole body appeared, and vasopressor was administered due to low blood pressure. On Day 7, since there were few findings suggestive of infection from cultural examinations and imaging tests, it was considered to be a non - infectious fever and we diagnosed as CRS. Symptoms included decreased oxygenation, decreased urine volume, declined renal function (creatinine 2.03 mg / dl), increased CRP (21.49 mg / dL), increased procalcitonin (63.6 ng/mL). Corticosteroid could not improve severe CRS, therefore, on Day 9, Tocilizumab 4 mg / kg was administered as CRS. An antipyretic effect was observed immediately after administration, and general condition was gradually improved. On Day 11, neutrophil engraftment was achieved.
Results
We examined the lymphocyte subset of CD4 T, CD8 T, Foxp3+Helios+Treg and their expressions of CD62L and CD45RA. The CD8/CD4 ratio was increased at the peak of CRS (68.4%/15.3% of lymphocytes) as compared to the baseline (18.5%/42.2%). Both CD4 and CD8 T cells at CRS dominantly consisted of CD62L-CD45RA-Effector-memory phenotype but it was more evident in CD8 T cells (52.3% in CD4 T, 79.5% in CD8 T). After the treatment with Tocilizumab, CD8/CD4 ratio decreased (26.6%/14.9%) and CD62L-CD45RA- Effector-memory phenotype also decreased (22.7% in CD4 T, 64.7% in CD8 T). %Foxp3+Helios+Tregs of CD4 T cells was stable in the peritransplant period (9.1 % before SCT, 8.3 % at the point of CRS and 8.3 % 1 month after SCT).
Conclusion
These results suggested that the sequence of PD-1 blockade and Auto-SCT could induce the aberrant enhancement of CD8-positive effector-memory cytotoxic T cells regardless of the adequate amount of Tregs leading to severe CRS and anti-IL-6 therapy can restore the abnormal lymphocyte activation and CRS symptoms. The careful monitoring of early T cell reconstitution after Auto-SCT following PD-1 blockade might provide a novel strategy to predict and control excessive immune reaction leading to severe CRS.
Session topic: 23. Stem cell transplantation - Clinical
Keyword(s): Autologous hematopoietic stem cell transplantation, Cytokine
Abstract: PB2484
Type: Publication Only
Background
Cytokine release syndrome (CRS) is a severe toxicity which is associated with the elevation of inflammatory cytokines and presumably with the activation of T cells. PD-1 is one of immune checkpoint molecules expressed on activated T cells and its immune regulation is thought to be the important target for anticancer therapy. Recent studies reported that patients received allogeneic stem cell transplantation (Allo-SCT) after PD-1 blockade often developed severe CRS followed by refractory GVHD. However, the safety of the treatment sequence of PD-1 blockade and autologous stem cell transplantation (Auto-SCT) has not been reported so far.
Aims
We demonstrate a case study about severe CRS after Auto-SCT with pretreatment by Nivolumab to characterize the abnormality of lymphoid immune reaction and clinical findings after the therapeutic combination.
Methods
A 63-year-old man was diagnosed with classical Hodgkin lymphoma (HD). His disease was resistant to several lines of chemotherapies including ABVD, DHAP, IDEA (Ifosphamide, Dexamethasone Etoposide and Cytarabine) and Brentuximab Vedotin. However, the disease was progressed with the enlargement of left subclavian lymph node. He received 22 courses of Nivolumab and achieved PR again. Consequently, he received Auto-SCT with LEED. On Day 5, he became febrile to 38.5℃ and was administered anti-biotics as febrile neutropenia. On Day 6, body temperature rise of up to 40℃, erythema of the whole body appeared, and vasopressor was administered due to low blood pressure. On Day 7, since there were few findings suggestive of infection from cultural examinations and imaging tests, it was considered to be a non - infectious fever and we diagnosed as CRS. Symptoms included decreased oxygenation, decreased urine volume, declined renal function (creatinine 2.03 mg / dl), increased CRP (21.49 mg / dL), increased procalcitonin (63.6 ng/mL). Corticosteroid could not improve severe CRS, therefore, on Day 9, Tocilizumab 4 mg / kg was administered as CRS. An antipyretic effect was observed immediately after administration, and general condition was gradually improved. On Day 11, neutrophil engraftment was achieved.
Results
We examined the lymphocyte subset of CD4 T, CD8 T, Foxp3+Helios+Treg and their expressions of CD62L and CD45RA. The CD8/CD4 ratio was increased at the peak of CRS (68.4%/15.3% of lymphocytes) as compared to the baseline (18.5%/42.2%). Both CD4 and CD8 T cells at CRS dominantly consisted of CD62L-CD45RA-Effector-memory phenotype but it was more evident in CD8 T cells (52.3% in CD4 T, 79.5% in CD8 T). After the treatment with Tocilizumab, CD8/CD4 ratio decreased (26.6%/14.9%) and CD62L-CD45RA- Effector-memory phenotype also decreased (22.7% in CD4 T, 64.7% in CD8 T). %Foxp3+Helios+Tregs of CD4 T cells was stable in the peritransplant period (9.1 % before SCT, 8.3 % at the point of CRS and 8.3 % 1 month after SCT).
Conclusion
These results suggested that the sequence of PD-1 blockade and Auto-SCT could induce the aberrant enhancement of CD8-positive effector-memory cytotoxic T cells regardless of the adequate amount of Tregs leading to severe CRS and anti-IL-6 therapy can restore the abnormal lymphocyte activation and CRS symptoms. The careful monitoring of early T cell reconstitution after Auto-SCT following PD-1 blockade might provide a novel strategy to predict and control excessive immune reaction leading to severe CRS.
Session topic: 23. Stem cell transplantation - Clinical
Keyword(s): Autologous hematopoietic stem cell transplantation, Cytokine