A 20-year-old male with no past medical history presented with acute hypoxic respiratory failure requiring intubation. CT scans revealed a 9.1 x 7.3 cm mediastinal mass encasing the aortic arch with extension into the lower neck resulting in tracheal deviation. Laboratory evaluation demonstrated a white blood cell count of 2.5 x 109/L with 78% blasts on differential, hemoglobin 7.1 g/dL, and platelets 51 x 109/L. Bone marrow evaluation revealed a hypercellular marrow with 98% blasts by morphology. By flow cytometry, blasts expressed CD34, CD117, CD33, CD38, CD56, and CD7 and lacked expression of myeloperoxidase (MPO) and monocytic markers. A subset of blasts expressed low levels of cytoplasmic CD3 although subsequent assessment by immunohistochemistry for CD3 was negative. The blasts were negative for CD2, CD4, CD5, CD8, CD19, and cCD79a. Cytogenetic analysis revealed 10 metaphases with a complex karyotype including rearrangement of chromosome 4, loss of chromosomes 12 and 13, and a rearrangement between chromosome 13 and 1-2 unidentified markers. Molecular testing was positive for a FLT3-ITD mutation. A fine needle aspiration of the mediastinal mass demonstrated acute leukemia with an immunophenotype similar to that of the bone. T-cell gene rearrangement analysis by PCR on the mediastinal biopsy showed no evidence of clonal T-cell gene rearrangement. While it was difficult to assign a definite lineage for this acute leukemia, diagnostic considerations included acute myeloid leukemia (AML), T-ALL, and mixed phenotype acute leukemia T/myeloid (MPAL). To meet criteria for MPAL T/myeloid, blasts must express lineage-defining markers for both T and myeloid lineages. This acute leukemia lacked MPO as well as monocytic markers and therefore did not meet criteria for the myeloid component of MPAL T/myeloid. While flow cytometry demonstrated weak cytoplasmic CD3 on the blasts suggestive of T-lineage differentiation, this could not be confirmed by immunohistochemical stains. Additionally, the blasts lacked expression of CD2, CD4, CD5, CD8, and CD1a. Therefore, a diagnosis of AML, NOS was initially favored.
The patient was induced with daunorubicin in combination with high-dose cytarabine and achieved complete remission (CR). He was consolidated with 2 cycles of high-dose cytarabine and in light of the FLT3-ITD mutation, sorafenib was added. Because his leukemia was considered "poor-risk" given the extramedullary disease at presentation, complex karyotype, and FLT3-ITD mutation, he underwent a 7/10 haploidentical allogeneic hematopoietic cell transplant (alloHCT) from his father in first remission. Conditioning included fludarabine, cyclophosphamide, and low-dose total body irradiation as per the standard Hopkins regimen. Prior to alloHCT, multiparameter flow cytometry from the University of Washington showed no evidence of measurable residual disease (MRD). Posttransplant immunosuppression consisted of cyclophosphamide, tacrolimus, and mycophenolate mofetil. A bone marrow biopsy and restaging PET CT at approximately day +60 confirmed an ongoing CR and 100% donor chimerism in the CD3, CD14/15, and CD19 compartments. For posttransplant maintenance, he received 6 cycles azacitidine (given daily for 5 days at 32 mg/m2 in 28-day cycles):initiated at approximately day +100:followed by maintenance sorafenib 200 mg twice daily. His tacrolimus was discontinued at approximately 6 months posttransplant with no evidence at any point of either acute or chronic graft-versus-host disease (GVHD).
At 13 months posttransplant, he developed progressive neutropenia. Bone marrow evaluation revealed relapsed leukemia with 42% blasts expressing a slightly different immunophenotype than that of his original disease (CD117-negative and CD5-positive). Immunohistochemical stains on the core biopsy demonstrated that blasts were positive for CD34, TdT, CD5, and CD7, with a small subset that was weakly positive for CD3. Cytogenetic studies demonstrated a complex karyotype similar to that of his original leukemia. FLT3-ITD PCR was negative but extended mutational testing:not previously performed:revealed mutations in FBXW7, NOTCH1, and EZH2, all of which are recurrently mutated in T-ALL. Additionally, bone marrow chimerism studies showed for the first time a decline in CD3 donor chimerism from 100% to 91%.
Based on emerging data to support the use of venetoclax in T-ALL, he began salvage therapy with venetoclax (given daily, initially at 800 mg then dose reduced to 400 mg due to the interaction with his azole for fungal prophylaxis) in combination with decitabine (given daily for 5 days at 20 mg/m2 in 28-day cycles). After 2 cycles, his peripheral blood counts had normalized, formal CR criteria were met, and a restaging bone marrow evaluation demonstrated no morphologic evidence of residual leukemia. MRD assessment:again performed via multiparameter flow cytometry at the University of Washington:also showed no evidence of persistent disease. CD3 chimerism in the bone marrow was restored to 100% donor.
In light of the lymphoid origin of his relapsed leukemia, next generation sequencing (NGS) was performed (ClonoSEQ, Adaptive Biosciences) on his relapse specimen, identifying a dominant T-cell receptor (TCR) clone comprising 8.249% of total nucleated cells. We retrospectively also assessed his original diagnostic bone marrow specimen and found that the same TCR clone was present in 11% of total nucleated cells. MRD assessment from a bone marrow specimen after 2 cycles of venetoclax and decitabine:also via ClonoSEQ:showed no detectable residual leukemia at a sensitivity of 1 leukemic cell per 106 cells. He received a total of 5 cycles of decitabine and venetoclax, with intermittent dose interruptions of venetoclax due to neutropenia. He remained MRD negative via multiparameter flow cytometry and ClonoSEQ and subsequently underwent a second haploidentical alloHCT with fludarabine, cyclophosphamide, and low-dose TBI conditioning. Decitabine and venetoclax were discontinued shortly prior to the second haploidentical alloHCT. He achieved full donor chimerism at day +18 posttransplant and continues in follow-up.