Presentation, diagnosis, and management of hematologic SMNs
| . | AML/MDS . | AML . | MDS . |
|---|---|---|---|
| Oncologic history | History of Li Fraumeni syndrome with very high-risk B-ALL diagnosed at age 18 y; attempt at curative frontline therapy with CD19 CAR T cells in hope of lesser toxicity compared with myeloablative regimen because of Li Fraumeni–associated risks; because of early loss of B-cell aplasia after CD19 CAR T-cell therapy at 4 mo, received CD19 CAR T-cell reinfusion, with subsequent development of MDS (chromosome 5 changes) 2 mo later; underwent unrelated cord blood HSCT for MDS using busulfan, fludarabine, and thiotepa–based conditioning regimen | History of disseminated B-lymphoblastic lymphoma (TCF-PBX1 translocation) diagnosed at age 10 y, including involvement of multiple cranial nerves; required emergency cranial XRT (2350 cGy) and boost (1500 cGy); isolated CNS relapse of B-lymphoblasts 2.5 y after initial diagnosis; received triple IT therapy and VCR/MTX as bridging therapy; received CD19 CAR T cells in first relapse | History of with B-ALL (unknown cytogenetics) diagnosed at age 10 y; first relapse was very early; received salvage chemotherapy followed by unrelated cord blood HSCT with TBI-based myeloablative conditioning regimen (TBI, etoposide, and CTX); second relapse was 2.5 y post-HSCT; received bridging chemotherapy while awaiting CD19 CAR T-cell infusion |
| Total radiation exposure (TBI), cGy | None | 2850 (CNS only) | 1200 |
| Brief CAR T-cell therapy course | Received lymphodepleting chemotherapy with CTX and fludarabine before CD19 CAR T cells, without significant complications; good count recovery but developed early loss of B-cell aplasia and received CD19 CAR T-cell reinfusion | Received lymphodepleting chemotherapy with CTX and fludarabine before CD19 CAR T cells; achieved MRD− CR; continued B-cell aplasia | Received lymphodepleting chemotherapy with CTX and fludarabine before CD19 CAR T cells; achieved MRD− CR; continued B-cell aplasia until time of SMN diagnosis |
| CAR T-cell construct | CD19/BB | CD19/BB | CD19/BB |
| HSCT (before/after CD19 CAR T-cell therapy) | Yes, after | NA | Yes, before |
| Presenting symptoms | Progressive cytopenias (trilineage) after full count recovery after first CD19 CAR T-cell treatment and early post-HSCT; fatigue | Developed worsening pancytopenia 18 mo post–CD19 CAR T-cell therapy | Progressive thrombocytopenia and new fevers 13 mo post–CD19 CAR T-cell therapy |
| Diagnosis | Bone marrow evaluation: MDS/AML with loss of original clone and new cytogenetics consisting of translocation(5;17)/AML | Bone marrow evaluation: AML NPM1+ and CEBPA+; negative for TCF3-PBX1 translocation | Bone marrow evaluation: MDS (RAEB-2), trisomy 8 and 9; MDS was XY and thought to be derived from cord blood |
| Management | Therapy with venetoclax/azacytidine to control disease; not eligible for second HSCT because of pulmonary GVHD/IPS complications from first HSCT | Therapy with CPX-351 (liposomal daunorubicin and cytarabine) and FLAG, then proceeded to 10/10 HLA-matched unrelated donor HSCT; myeloablative conditioning regimen with busulfan, fludarabine, and thiotepa | Therapy with azacitidine, then mismatched sibling HSCT; myeloablative conditioning regimen with busulfan and melphalan |
| Outcome | Patient died of refractory MDS/AML with minimal response to therapy and progressive IPS post-HSCT at ∼3 mo post-HSCT | Alive without disease 14 mo post-HSCT | Alive without disease 18 mo post–second HSCT |
| . | AML/MDS . | AML . | MDS . |
|---|---|---|---|
| Oncologic history | History of Li Fraumeni syndrome with very high-risk B-ALL diagnosed at age 18 y; attempt at curative frontline therapy with CD19 CAR T cells in hope of lesser toxicity compared with myeloablative regimen because of Li Fraumeni–associated risks; because of early loss of B-cell aplasia after CD19 CAR T-cell therapy at 4 mo, received CD19 CAR T-cell reinfusion, with subsequent development of MDS (chromosome 5 changes) 2 mo later; underwent unrelated cord blood HSCT for MDS using busulfan, fludarabine, and thiotepa–based conditioning regimen | History of disseminated B-lymphoblastic lymphoma (TCF-PBX1 translocation) diagnosed at age 10 y, including involvement of multiple cranial nerves; required emergency cranial XRT (2350 cGy) and boost (1500 cGy); isolated CNS relapse of B-lymphoblasts 2.5 y after initial diagnosis; received triple IT therapy and VCR/MTX as bridging therapy; received CD19 CAR T cells in first relapse | History of with B-ALL (unknown cytogenetics) diagnosed at age 10 y; first relapse was very early; received salvage chemotherapy followed by unrelated cord blood HSCT with TBI-based myeloablative conditioning regimen (TBI, etoposide, and CTX); second relapse was 2.5 y post-HSCT; received bridging chemotherapy while awaiting CD19 CAR T-cell infusion |
| Total radiation exposure (TBI), cGy | None | 2850 (CNS only) | 1200 |
| Brief CAR T-cell therapy course | Received lymphodepleting chemotherapy with CTX and fludarabine before CD19 CAR T cells, without significant complications; good count recovery but developed early loss of B-cell aplasia and received CD19 CAR T-cell reinfusion | Received lymphodepleting chemotherapy with CTX and fludarabine before CD19 CAR T cells; achieved MRD− CR; continued B-cell aplasia | Received lymphodepleting chemotherapy with CTX and fludarabine before CD19 CAR T cells; achieved MRD− CR; continued B-cell aplasia until time of SMN diagnosis |
| CAR T-cell construct | CD19/BB | CD19/BB | CD19/BB |
| HSCT (before/after CD19 CAR T-cell therapy) | Yes, after | NA | Yes, before |
| Presenting symptoms | Progressive cytopenias (trilineage) after full count recovery after first CD19 CAR T-cell treatment and early post-HSCT; fatigue | Developed worsening pancytopenia 18 mo post–CD19 CAR T-cell therapy | Progressive thrombocytopenia and new fevers 13 mo post–CD19 CAR T-cell therapy |
| Diagnosis | Bone marrow evaluation: MDS/AML with loss of original clone and new cytogenetics consisting of translocation(5;17)/AML | Bone marrow evaluation: AML NPM1+ and CEBPA+; negative for TCF3-PBX1 translocation | Bone marrow evaluation: MDS (RAEB-2), trisomy 8 and 9; MDS was XY and thought to be derived from cord blood |
| Management | Therapy with venetoclax/azacytidine to control disease; not eligible for second HSCT because of pulmonary GVHD/IPS complications from first HSCT | Therapy with CPX-351 (liposomal daunorubicin and cytarabine) and FLAG, then proceeded to 10/10 HLA-matched unrelated donor HSCT; myeloablative conditioning regimen with busulfan, fludarabine, and thiotepa | Therapy with azacitidine, then mismatched sibling HSCT; myeloablative conditioning regimen with busulfan and melphalan |
| Outcome | Patient died of refractory MDS/AML with minimal response to therapy and progressive IPS post-HSCT at ∼3 mo post-HSCT | Alive without disease 14 mo post-HSCT | Alive without disease 18 mo post–second HSCT |
AML, acute myeloid leukemia; CNS, central nervous system; CR, complete remission; FLAG, fludarabine, cytarabine, and filgrastim; GVHD, graft-versus-host disease; IPS, idiopathic pneumonia syndrome; IT, intrathecal; MDS, myelodysplastic syndrome; MRD, minimal residual disease; MTX, methotrexate; NA, not applicable; RAEB-2, refractory anemia with excess blasts type 2; VCR, vincristine; XRT, radiation therapy.