Results
A previously healthy 4-year-old girl presented with fever. Physical exam at presentation was normal; laboratory studies demonstrated a white blood cell count of 3820 cells/µL with 6% circulating blasts, absolute neutrophil count 640 cells/µL, hemoglobin 11.5 g/dL and platelets 74,000 cells/µL. Bone marrow (BM) testing was diagnostic for MDS with excess blasts-2 (Figure 1). Next generation sequencing panel showed PTPN11 p.A72V, 32% of 1331 reads and WT1 p.S382-frameshift, 17% of 848 reads. Fluorescence in situ hybridization (FISH) detected monosomy 7. An underlying germline disorder, which is present in at least 30% of pediatric MDS cases3, was not identified. Extensive testing included telomere lengths, chromosome breakage, pancreas iso-amylase and whole exome sequencing.
She received decitabine (20 mg/m2 for 10 days); follow-up BM evaluation demonstrated a reduction in blasts to 3% with persistent multilineage dysplasia (Figure 2A, B). She proceeded to HCT conditioned with myeloablative busulfan and cyclophosphamide followed by BM graft from her 10/10 HLA matched father (5.84x106CD34+ cell/kg) (Figure 2C). Graft versus host disease (GvHD) prophylaxis included cyclosporine and methotrexate. Engraftment occurred on day 28 and she experienced minimal transplant associated toxicities and no GvHD. BM evaluation on day 30 was without evidence of MDS. However, surveillance BM on day 60 (7 months post diagnosis) demonstrated recurrent disease (Figure 2B). Cyclosporine was rapidly weaned followed by treatment with azacytidine (75 mg/m2 for 7 days) and DLI (1 x 106 CD3+ T cells/kg). Salvage treatment with azacytidine in combination with fludarabine / cytarabine / granulocyte- growth-factor led to a measurable residual disease (MRD) negative remission. Maintenance therapy was initiated with azacytidine (75mg/m2 for 7 days, 28-day cycles) and DLI every other cycle (3 x 106 CD3+ T cells/kg for cycle 1, 2 x 107 CD3+ T cells/kg for cycle 3). Remission was maintained for 4 cycles, until she developed bone pain and recurrent cytopenia. A BM evaluation demonstrated second recurrence of MDS (17 months post diagnosis). She received venetoclax (14mg/kg, 800 mg adult equivalent) combined with cytarabine (1000 mg/m2 IV every 12 hours for 5 days). BM performed on day 22 of treatment was acellular and venetoclax was held. Repeat BM assessment on day 42 showed remission by flow cytometry and the patient proceeded to second HCT using a 10/10 HLA matched unrelated donor (2.75 x 106CD34+ cells/kg) after fludarabine, clofarabine and busulfan conditioning. Engraftment occurred on day 16. The second HCT was uncomplicated; CD34 chimerism was 100% donor 2 on day 30 and cyclosporine was weaned by 186 days post HCT. She remained disease-free until one year post second transplant when routine surveillance demonstrated 70% peripheral blasts consistent with transformation to AML/MDS (~32 months after diagnosis). Re-induction with cytarabine and fludarabine resulted in MRD negative remission. An experimental cellular therapy did not mediate a durable remission. She relapsed for a fourth time with a significant blast burden (MDS/AML) and received CPX-351 with the goal to achieve disease control prior to a planned investigational 3rd HCT. Her disease was refractory to this re-induction attempt and treatment goals were transitioned to palliative approaches.