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.