ACQUIRED HYPER-IGM SYNDROME FOLLOWING CD20 MAB THERAPY FOR EPSTEIN-BARR VIRUS (EBV) REACTIVATION POST-ALLOGENEIC STEM CELL TRANSPLANT (ALLO-SCT)
(Abstract release date: 05/19/16)
EHA Library. Tambaro F. 06/09/16; 135074; PB2174
Dr. Francesco Paolo Tambaro
Contributions
Contributions
Abstract
Abstract: PB2174
Type: Publication Only
Background
EBV reactivation can be a complication of allogeneic stem cell transplant (allo-SCT) that may lead to EBV-related B Cell Post Transplant Lymphoproliferative Disorder (PTLD).Preemptive treatment with the CD20 mAb rituximab eliminates CD20+ lymphocytes, thereby blocking virus replication, is indicated for rising EBV viral load.
Aims
Here we report 2 cases of acquired hyper-IgM syndrome as a late complication in kids who underwent allo-SCT and received rituximab for treatment of EBV reactivation.
Methods
An 11 yo boy and 8 yo girl underwent allo-SCT in 10/2008 and 8/2010 for ALL and Hemophagocytic Lymphohistiocytosis (HLH), respectively. Patient (pt) and allo-SCT characteristics are shown (Table).
Results
EBV reactivation occurred on day +59 and +33 with 34860 and 40325 EBV DNA copies in the pt with ALL and HLH, respectively. Pts received rituximab (Table) with complete elimination of viremia. Both pts developed hypogammaglobulinemia (IgM, IgG and IgA) post-transplant and received IVIG (0.5 g/kg) monthly for the first 3 months after transplant, then every 3 months, thereafter. The pts developed recurrent sino-pulmonary and enteric infections treated with antibiotics beginning 30 and 18 months post-all-SCT for the ALL and HLH pts, respectively (Figure). In the setting of these recurrent infections, and supportive IVIG, both pts developed progressive increase in IgM level. The ALL pt began to lose full donor chimerism, with no evidence of ALL relapse. He also had recurrent autoimmune thrombocytopenia, which responded to IVIG.Neither pt nor respective donor had mutation in CD154. Flow cytometry for the ALL pt showed decreased mature lymphocytes (CD19+ IgG+), memory lymphocytes (CD19+CD27+IgM+), switched memory (CD19+CD27+IgM-), and transitional lymphocytes (CD 19+CD27+IgM+), and no plasma cells in blood. Flow cytometry studies are ongoing for the HLH pt.
Conclusion
We hypothesize that both EBV and rituximab played roles in development of these cases. EBV is responsible of B cell proliferation, maturation arrest, defective DNA repair, leading to hematological neoplasms. EBV infection and reactivation are also associated with autoimmune disorders, transiently elevated IgM during viremia, and monoclonal gammopathy after allo-SCT. Preemptive treatment with rituximab eliminates CD20+ cells where the virus replicates, thereby blocking EBV proliferation, but reduces lymphocyte counts for more than 6 months post BMT, which can alter immunological surveillance. These cases demonstrate development of acquired hyper-IgM syndrome as a late complication of EBV reactivation treated with rituximab post-allo-SCT, which is not previously described. We recommend diligent prolonged monitoring of IgM level post-allo-SCT, particularly in patients who develop autoimmune cytopenia or recurrent infections.
Session topic: E-poster
Keyword(s): EBV, Immune deficiency, Immunoglobulin, Rituximab
Type: Publication Only
Background
EBV reactivation can be a complication of allogeneic stem cell transplant (allo-SCT) that may lead to EBV-related B Cell Post Transplant Lymphoproliferative Disorder (PTLD).Preemptive treatment with the CD20 mAb rituximab eliminates CD20+ lymphocytes, thereby blocking virus replication, is indicated for rising EBV viral load.
Aims
Here we report 2 cases of acquired hyper-IgM syndrome as a late complication in kids who underwent allo-SCT and received rituximab for treatment of EBV reactivation.
Methods
An 11 yo boy and 8 yo girl underwent allo-SCT in 10/2008 and 8/2010 for ALL and Hemophagocytic Lymphohistiocytosis (HLH), respectively. Patient (pt) and allo-SCT characteristics are shown (Table).
Results
EBV reactivation occurred on day +59 and +33 with 34860 and 40325 EBV DNA copies in the pt with ALL and HLH, respectively. Pts received rituximab (Table) with complete elimination of viremia. Both pts developed hypogammaglobulinemia (IgM, IgG and IgA) post-transplant and received IVIG (0.5 g/kg) monthly for the first 3 months after transplant, then every 3 months, thereafter. The pts developed recurrent sino-pulmonary and enteric infections treated with antibiotics beginning 30 and 18 months post-all-SCT for the ALL and HLH pts, respectively (Figure). In the setting of these recurrent infections, and supportive IVIG, both pts developed progressive increase in IgM level. The ALL pt began to lose full donor chimerism, with no evidence of ALL relapse. He also had recurrent autoimmune thrombocytopenia, which responded to IVIG.Neither pt nor respective donor had mutation in CD154. Flow cytometry for the ALL pt showed decreased mature lymphocytes (CD19+ IgG+), memory lymphocytes (CD19+CD27+IgM+), switched memory (CD19+CD27+IgM-), and transitional lymphocytes (CD 19+CD27+IgM+), and no plasma cells in blood. Flow cytometry studies are ongoing for the HLH pt.
| Pt 1 | Pt 2 | |
| Diagnosis/SEX | ALL/ Male | HLH /Female |
| Conditioning Regimen | TBI Thyotepa Cyclophospamide ATG | Busulphan Cyclophospamide ATG |
| GVHD prophylaxis | CSA MTX | CSA |
| Donor | MRD (10/10) | MRD 9/10 |
| Cell source/ CD 34+ x 108/kg | BM / 4.7 | BM / 4.5 |
| PLT day / ANC day | +14 /+14 | +19 /+19 |
| Infections | None | Staph. Warneri |
| aGVHD/Grade/organ | II skin | II skin |
| GVHD treatment | MPDN 0.5mg/kg | MPDN 1mg/kg |
| EBV reactivation day /copies | +59/34860 | +33/40325 |
| EBV treatment | Rituximab 375 mg/m2x 3 weeks | Rituximab 375 mg/m2x 2 weeks |
Conclusion
We hypothesize that both EBV and rituximab played roles in development of these cases. EBV is responsible of B cell proliferation, maturation arrest, defective DNA repair, leading to hematological neoplasms. EBV infection and reactivation are also associated with autoimmune disorders, transiently elevated IgM during viremia, and monoclonal gammopathy after allo-SCT. Preemptive treatment with rituximab eliminates CD20+ cells where the virus replicates, thereby blocking EBV proliferation, but reduces lymphocyte counts for more than 6 months post BMT, which can alter immunological surveillance. These cases demonstrate development of acquired hyper-IgM syndrome as a late complication of EBV reactivation treated with rituximab post-allo-SCT, which is not previously described. We recommend diligent prolonged monitoring of IgM level post-allo-SCT, particularly in patients who develop autoimmune cytopenia or recurrent infections.
Session topic: E-poster
Keyword(s): EBV, Immune deficiency, Immunoglobulin, Rituximab
Abstract: PB2174
Type: Publication Only
Background
EBV reactivation can be a complication of allogeneic stem cell transplant (allo-SCT) that may lead to EBV-related B Cell Post Transplant Lymphoproliferative Disorder (PTLD).Preemptive treatment with the CD20 mAb rituximab eliminates CD20+ lymphocytes, thereby blocking virus replication, is indicated for rising EBV viral load.
Aims
Here we report 2 cases of acquired hyper-IgM syndrome as a late complication in kids who underwent allo-SCT and received rituximab for treatment of EBV reactivation.
Methods
An 11 yo boy and 8 yo girl underwent allo-SCT in 10/2008 and 8/2010 for ALL and Hemophagocytic Lymphohistiocytosis (HLH), respectively. Patient (pt) and allo-SCT characteristics are shown (Table).
Results
EBV reactivation occurred on day +59 and +33 with 34860 and 40325 EBV DNA copies in the pt with ALL and HLH, respectively. Pts received rituximab (Table) with complete elimination of viremia. Both pts developed hypogammaglobulinemia (IgM, IgG and IgA) post-transplant and received IVIG (0.5 g/kg) monthly for the first 3 months after transplant, then every 3 months, thereafter. The pts developed recurrent sino-pulmonary and enteric infections treated with antibiotics beginning 30 and 18 months post-all-SCT for the ALL and HLH pts, respectively (Figure). In the setting of these recurrent infections, and supportive IVIG, both pts developed progressive increase in IgM level. The ALL pt began to lose full donor chimerism, with no evidence of ALL relapse. He also had recurrent autoimmune thrombocytopenia, which responded to IVIG.Neither pt nor respective donor had mutation in CD154. Flow cytometry for the ALL pt showed decreased mature lymphocytes (CD19+ IgG+), memory lymphocytes (CD19+CD27+IgM+), switched memory (CD19+CD27+IgM-), and transitional lymphocytes (CD 19+CD27+IgM+), and no plasma cells in blood. Flow cytometry studies are ongoing for the HLH pt.
Conclusion
We hypothesize that both EBV and rituximab played roles in development of these cases. EBV is responsible of B cell proliferation, maturation arrest, defective DNA repair, leading to hematological neoplasms. EBV infection and reactivation are also associated with autoimmune disorders, transiently elevated IgM during viremia, and monoclonal gammopathy after allo-SCT. Preemptive treatment with rituximab eliminates CD20+ cells where the virus replicates, thereby blocking EBV proliferation, but reduces lymphocyte counts for more than 6 months post BMT, which can alter immunological surveillance. These cases demonstrate development of acquired hyper-IgM syndrome as a late complication of EBV reactivation treated with rituximab post-allo-SCT, which is not previously described. We recommend diligent prolonged monitoring of IgM level post-allo-SCT, particularly in patients who develop autoimmune cytopenia or recurrent infections.
Session topic: E-poster
Keyword(s): EBV, Immune deficiency, Immunoglobulin, Rituximab
Type: Publication Only
Background
EBV reactivation can be a complication of allogeneic stem cell transplant (allo-SCT) that may lead to EBV-related B Cell Post Transplant Lymphoproliferative Disorder (PTLD).Preemptive treatment with the CD20 mAb rituximab eliminates CD20+ lymphocytes, thereby blocking virus replication, is indicated for rising EBV viral load.
Aims
Here we report 2 cases of acquired hyper-IgM syndrome as a late complication in kids who underwent allo-SCT and received rituximab for treatment of EBV reactivation.
Methods
An 11 yo boy and 8 yo girl underwent allo-SCT in 10/2008 and 8/2010 for ALL and Hemophagocytic Lymphohistiocytosis (HLH), respectively. Patient (pt) and allo-SCT characteristics are shown (Table).
Results
EBV reactivation occurred on day +59 and +33 with 34860 and 40325 EBV DNA copies in the pt with ALL and HLH, respectively. Pts received rituximab (Table) with complete elimination of viremia. Both pts developed hypogammaglobulinemia (IgM, IgG and IgA) post-transplant and received IVIG (0.5 g/kg) monthly for the first 3 months after transplant, then every 3 months, thereafter. The pts developed recurrent sino-pulmonary and enteric infections treated with antibiotics beginning 30 and 18 months post-all-SCT for the ALL and HLH pts, respectively (Figure). In the setting of these recurrent infections, and supportive IVIG, both pts developed progressive increase in IgM level. The ALL pt began to lose full donor chimerism, with no evidence of ALL relapse. He also had recurrent autoimmune thrombocytopenia, which responded to IVIG.Neither pt nor respective donor had mutation in CD154. Flow cytometry for the ALL pt showed decreased mature lymphocytes (CD19+ IgG+), memory lymphocytes (CD19+CD27+IgM+), switched memory (CD19+CD27+IgM-), and transitional lymphocytes (CD 19+CD27+IgM+), and no plasma cells in blood. Flow cytometry studies are ongoing for the HLH pt.
| Pt 1 | Pt 2 | |
| Diagnosis/SEX | ALL/ Male | HLH /Female |
| Conditioning Regimen | TBI Thyotepa Cyclophospamide ATG | Busulphan Cyclophospamide ATG |
| GVHD prophylaxis | CSA MTX | CSA |
| Donor | MRD (10/10) | MRD 9/10 |
| Cell source/ CD 34+ x 108/kg | BM / 4.7 | BM / 4.5 |
| PLT day / ANC day | +14 /+14 | +19 /+19 |
| Infections | None | Staph. Warneri |
| aGVHD/Grade/organ | II skin | II skin |
| GVHD treatment | MPDN 0.5mg/kg | MPDN 1mg/kg |
| EBV reactivation day /copies | +59/34860 | +33/40325 |
| EBV treatment | Rituximab 375 mg/m2x 3 weeks | Rituximab 375 mg/m2x 2 weeks |
Conclusion
We hypothesize that both EBV and rituximab played roles in development of these cases. EBV is responsible of B cell proliferation, maturation arrest, defective DNA repair, leading to hematological neoplasms. EBV infection and reactivation are also associated with autoimmune disorders, transiently elevated IgM during viremia, and monoclonal gammopathy after allo-SCT. Preemptive treatment with rituximab eliminates CD20+ cells where the virus replicates, thereby blocking EBV proliferation, but reduces lymphocyte counts for more than 6 months post BMT, which can alter immunological surveillance. These cases demonstrate development of acquired hyper-IgM syndrome as a late complication of EBV reactivation treated with rituximab post-allo-SCT, which is not previously described. We recommend diligent prolonged monitoring of IgM level post-allo-SCT, particularly in patients who develop autoimmune cytopenia or recurrent infections.
Session topic: E-poster
Keyword(s): EBV, Immune deficiency, Immunoglobulin, Rituximab
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