Results
Patient, disease and transplant characteristics:Twenty-three pediatric and young adult patients with myeloid
malignancies underwent allo-HCT following BU-FLU-MEL conditioning. The
clinical characteristics of the patients are outlined in Table
1 . The median age at transplant was 15.4 years (0.6 to 27.2 years).
Seventeen patients were male. Ethnic and/or racial minorities
constituted 48% of all patients, the majority of whom (35%) were
Hispanic.
Seventeen patients had AML with fourteen being de novo , one
evolving from MDS and two were treatment related (t-AML) secondary to
osteogenic and Ewings sarcoma therapy. The remaining patients included
four patients with MDS, two of which were treatment related secondary to
acute lymphoblastic leukemia (ALL) therapy, and two patients had chronic
myeloid leukemia (CML). Most AML patients were transplanted in first
remission (76%) while five MDS patients (including an MDS patient
evolving to AML) did not receive conventional chemotherapy prior to
conditioning (Table 1) . Cytogenetics were unfavorable in the
majority of AML/MDS patients (Table 1) while the pediatric
disease risk index (DRI) was intermediate in 71%, and high or very high
in 19%21. Two patients with CML are included in this
analysis, with one undergoing allo-HCT following accelerated phase while
the other had T315I mutation in the BCR-ABL1 kinase domain.
Seven patients received PBSCT from an HLA-matched sibling. Unrelated
donor allo-HCT included two patients who received a MUD PBSC graft, one
patient who received a UCB unit and two patients who were infused with
double UCB units. Eleven patients underwent T-cell replete haplo-BMT.
Engraftment and chimerism: All patients had trilineage
engraftment with complete donor chimerism on their day +28 bone marrows
biopsies. One patient who received haplo-BMT experienced secondary graft
failure after early CMV reactivation and treatment with ganciclovir. He
was salvaged 46 days after the initial transplant using a single day
conditioning regimen followed by infusion of unmanipulated G-CSF
mobilized PBSC from his original maternal donor and engrafted promptly
(day +14)22, 23. All patients when re-assessed by
peripheral blood chimerisms on days +100, +180 and +365 remained
complete donor chimeras.
Graft-versus-host disease: The cumulative incidence of
grades II-IV and III-IV acute GvHD (aGvHD) was 44.8% (Figure
1A) (MSD/MUD-PB 66.7% vs haplo-BMT 19.2%; P=0.039 )(Figure 1B) and 17.8% respectively (MSD/MUD-PB 33.3% vs
haplo-BMT 10%; P=0.196 ) (Figure 1B) . The cumulative
incidence of chronic GvHD (cGvHD) was 27.3% (Figure 1C)(MSD/MUD-PB 66.7% vs haplo-BMT 0%; P=0.002 ) (Figure
1D) and severe cGvHD was 9.1% respectively (Figure 1C ). Of
the six patients with cGVHD (1 mild, 3 moderate, 2 severe) three
previously had grade III-IV aGvHD, two had grade II aGvHD and one
developed de novo cGvHD seven months after MSD PBSCT while off
immunosuppression. Five of six patients required systemic steroid
therapy and three were also given ruxolitinib with
resolution/improvement of their cGvHD symptoms. Two patients continue on
cGvHD therapy.
Survival: Two patients (8.7%) required admission to the
intensive care unit (ICU) within their first 100 days post-allo-HCT. One
patient developed hyperammonemia due to Ureaplasma parvum with
metabolic encephalopathy necessitating intubation and mechanical
ventilation24. The other patient was transferred to
ICU because of mucositis needing brief intubation for airway support.
Only one patient with infant AML who underwent haplo-BMT (paternal
donor) in CR1 with 1.8% minimal residual disease (MRD)+ relapsed 13.6
months following transplantation resulting in a cumulative incidence of
relapse of 4.5%. This patient received a second haplo-BMT (maternal
donor) 16.6 months after the first and remains in remission without GvHD
8.2 months post second haplo-BMT. With a median follow-up of 39.6 months
(range 11 to 115 months) the OS is 100% and PFS 95.5% (Figure
1E ). Taking into consideration both relapse and grade III-IV acute or
chronic GvHD requiring systemic treatment, the GRFS is 67.8%
(Figure 1E ) with haplo-BMT recipients having significantly
improved GRFS 83.3% compared to 40% in patients receiving MSD or MUD
PBSCT (P=0.025 ) (Figure 1F ).