We show here that haploidentical HCT using PTCy is feasible and effective in treating non-malignant diseases, after a median follow-up of 20 months (range 4–71). The 2-year OS for patients with a variety of non-malignant diseases, including PID, inherited BMF syndromes, SAA, metabolic disorders, and hemoglobinopathy, was 89%. The 2-year GRFS in our cohort of 44 patients was 66%.
Our data compares favorably to the published literature on haploidentical HCT for children with non-malignant diseases. There are 4 relatively recent publications with more than 10 patients describing outcomes of haploidentical HCT in children with a variety of non-malignant diseases. In the study by Uppuluri and colleagues, 16 patients underwent haploidentical HCT for PID, at a median follow-up of 23.3 months, OS was 62.5% and grade II-IV was 50%.20 Benedicte et al. have reported the outcomes of haploidentical HCT for 27 patients with OS of 77% and grade II-IV aGvHD of 46% at a median follow-up of 25.6 months.19 Malhi and colleagues have reported the results of 23 patients using haploidentical HCT. After a median follow-up of 2.5 years, OS and EFS were 91% and 78%, respectively. Grade II-IV aGvHD was 78%.21 Olaya M et al. have reported outcomes of 47 patients with inborn errors of immunity using different donors. Nineteen patients underwent haploidentical HCT with an OS of 72%.15
In a univariate analysis model, the only factors associated with a better GRFS were transplantation at an age younger than 5 years and PID as an indication for HCT.27 This could reflect that early recognition and diagnosis of these diseases leads to less severe post-HCT complications with better survival outcomes. Active infections at the time of HCT have been known to be associated with poor survival in patients with PID. Moreover, we show that particularly patients with PID had 100% overall survival compared to other non-malignant diseases in our cohort. Although we did not find a significant improvement in survival over time, this could relate to allowing patients with more severe diseases to have access to transplant.
Eight patients developed GF. Four of the 8 patients proceeded to second HCT and are alive. Only age at HCT (after 5 years) showed a significant association with higher incidence of graft failure. Most patients with GF were transplanted for SAA (n = 6). This could be attributed to the risk of transfusion-induced sensitization to the HLA-haploidentical grafts.28,29 Interestingly, 3 out the 6 patients with SAA and GF had strong donor-specific antibodies and despite desensitization with intravenous immunoglobulins (IVIG), rituximab and plasmapheresis, they succumbed to GF. The limited sample size does not allow us to derive definitive recommendation on transplant conditioning regimen. The desire to lower toxicity and end organ damage is highly desirable when HCT is offered to children with non-malignant diseases. We did not show that RIC is associated with more GF. Hence, using RIC in patients with certain non-malignant diseases such as PID should be further investigated in prospective manner.
There is a general agreement that the incidence of acute and chronic GvHD must be kept to a minimum for HCT for non-malignant diseases. We observed an acceptable rates of GvHD as most of the patients had only grade 1 aGvHD and mild chronic GvHD. Haploidentical HCT using PTCy along with using serotherapy contributed to the low rates of GvHD in our cohort with no mortality from viral infections. The near universal approach in our center of using in vivo T-cell depletion prevented us from studying this further.
One limitation of our study is the retrospective design. Second, non-malignant diseases are a heterogeneous group with a diverse pathophysiology, making it difficult to select the best conditioning regimen for each disease.
In conclusion, our data show that in resource limited settings, and when HLA-identical donors are not available, haploidentical HCT using PTCy, is feasible and effective in curing children with various non-malignant diseases with acceptable rates of GvHD. GF remains an obstacle especially when anti-HLA antibodies are strongly present due to transfusion-induced sensitization, despite using desensitization techniques. With the expansion of HCT in children with non-malignant diseases and the improved outcomes and long-term survival, conditioning regimens can be further modified so as to ensure intact survival and low rates of GF. Reduced intensity conditioning needs to be further studied prospectively especially in patients with primary immunodeficiency.