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.