Results
Patient Demographics
Over the 18-year period from 2003 to 2020, 29 patients met eligibility
criteria. They were split into the targeted group which comprised of 17
subjects and the untargeted group which was made up of the remaining 12
subjects.
Patient Demographic data is presented in Table 1. The recipients had a
median age of 13 years (range 2-18 years) and 72% were male. All
patients were in morphologic remission at the time of transplant.
Fourteen patients (48%) were in CR1 and were transplanted due to
high-risk disease: Eight had persistently positive Minimal Residual
Disease (MRD), three were Philadelphia or Philadelphia like chromosome
positive, two had hypodiploid ALL and one patient had bi-phenotypic
leukemia. The remaining 15 (52%) were transplanted in CR2. Data on MRD
status prior to transplant was available for 25 subjects. Three-quarters
of this group (65% of the entire cohort) had a level below 0.01% by
flow cytometric analysis and were considered negative.
Engraftment
Neutrophil engraftment was seen in all patients at a median of 14 days
(range: 8-30 days). Platelet engraftment was successful in 28 of the 29
patients, the remaining one died prior to engraftment. The median time
to platelet engraftment was 16 days (range 0-89 days). Two patients had
engraftment beyond day 60, one of whom required continued platelet
infusion due to persistent hematuria.
Graft versus host disease
Fourteen of the 29 subjects developed grade 2 or higher aGvHD, resulting
in a cumulative incidence at day 100 of 44.8% (95% CI 35.6 – 54.0%).
Severe aGVHD (grade three or higher) was seen in six patients which gave
a cumulative incidence at day 100 of 20.7% (95% CI 9.9 – 40.3%).
Chronic graft versus host disease (cGvHD) was seen in four subjects. The
cumulative incidence of cGvHD at one year was 16.0% (95% CI 8.7% -
23.3%). cGvHD was graded as severe in three of the four subjects. All
three had pre-existing aGvHD.
Toxicity
CMV infection was documented in nine of 29 subjects in the cohort giving
a cumulative incidence of 31% (95% CI 22.4% - 39.6%) at one year.
The median time to reactivation was 24 days (IQR of 16 - 34 days). Two
of these 9 children had a primary infection. Clinically significant EBV
reactivations that required pre-emptive treatment were documented in
five of 27 patients for whom data was available. Culture proven
bacterial infections were documented in nine subjects within the first
100 days post-transplant. Gram-positive organisms were cultured in blood
in two-thirds of positive cases. Finally fungal infections were seen in
two subjects, both of whom developed oral thrush.
Grade three mucositis was seen in all 29 subjects in this analysis.
Sinusoidal obstructive syndrome (SOS) was seen in three of 20 patients
in the cohort for whom data was available. The cumulative incidence at
100 days post transplant was 15.0% (95% CI 7.0% - 23.0%). Only one
participant had severe SOS resulting in death from multi-organ
dysfunction.
Survival analysis
The median follow-up for the cohort was 3.25 years (1-10 years). There
were six deaths recorded, all occurring within two years of transplant
resulting in a 2-year overall survival for the entire cohort of 78.1%
(95% CI 70.8% - 86.4%). The Bu targeted group had a similar 2-year
overall survival calculated at 79.9% (95% CI 69.4% - 90.4%) compared
to the untargeted group which was 75.0% (95% CI 62.5% - 87.5%). This
difference did not reach statistical significance, p value = 0.6 (Figure
2).
In the subjects who succumbed, two deaths were due to progressive
disease post relapse, one patient was lost to SOS and another to causes
directly related to cGvHD. The remaining two children died due to
progressive organ dysfunction.
Overall, there were a total of seven events. No events occurred after 2
years of transplantation. This resulted in a 2-year EFS of 74.7% (95%
CI 66.4% – 83.0%). In the Bu targeted group, the 2-year EFS was
79.9% (95% CI 69.4% - 90.4%) compared to the untargeted group:
66.7% (95% CI 53.1% - 80.3%), p = 0.4. (Figure 3).
Three children in the cohort relapsed post-transplant, giving a
cumulative incidence of relapse at two years of 11.3% (95% CI 5.1% -
17.5%). One of the three children went on to receive a successful
second transplant (Figure 4).
The non-relapse mortality calculated at two years was 15.4% (95% CI
8.3% - 22.5%) for the entire group and was 15.4% (95% CI 5.4% -
25.4%) and 16.7% (95% CI 5.9% - 27.5%) p = 0.7 in the Bu targeted
and untargeted groups respectively (Figure 5).
Univariate analysis did not reveal any factors, including pre-transplant
MRD status, that correlated significantly with the risk of death or
relapse.