Excellent Outcomes in Children and Young Adults Using Reduced-Intensity Conditioning for Patients with Inborn Errors of Immunity, Hematopoiesis, and Metabolism with Single-Unit Cord Blood or Bone Marrow

Reduced-intensity conditioning (RIC) regimens have been shown to decrease transplant-related morbidity and mortality; however, this comes with an increased risk of graft failure and morbidity and mortality secondary to infections following intense serotherapy. Here we report a novel RIC regimen for chemotherapy-naïve patients. (Trial: NCT01852370). 

Between 2012 and 2015, 28 patients with non-malignant conditions underwent first hematopoietic cell transplantation (HCT) using either single-unit umbilical cord blood (UCB; n=23) or bone marrow (4 unrelated, 1 mismatched maternal donor) at the Children's Hospital of Pittsburgh of UPMC. Patients received alemtuzumab (0.7-2.2 mg/kg), hydroxyurea (30 mg/kg/day), fludarabine (150 mg/m²), melphalan (140 mg/m²), and thiotepa (200 mg/m²) with tacrolimus and mycophenolate mofetil as GVHD prophylaxis. Patient and graft characteristics are shown in the table.

Neutrophil engraftment occurred in all patients at a median of 14 days post-HCT. Platelet engraftment (>20K) occurred at a median of 35 days post-HCT in 24 of 25 evaluable patients. 1 patient developed graft failure prior to platelet engraftment, and 3 patients were not evaluable due to mucosal bleeding requiring prolonged transfusion (Table). 27 of 28 patients had >98% donor whole blood chimerism at first measurement, performed at a median of 28 days post-HCT. The median chimerism was 100% in whole blood (range: 50-100%; n=20) and T cell fraction (range: 0-100%; n=18) at 6 months post-HCT, and 100% (range: 83-100%; n=16) in whole blood and 100% (range: 71-100%; n=13) in the T cell fraction at 12 months. 1 patient had graft failure at day +38 and after autologous reconstitution, underwent a successful second single-unit umbilical cord blood transplant. No patient developed VOD, IPS, hemorrhagic cystitis, or pericardial effusion requiring drainage.

T cell reconstitution commenced between 100-180 days post-HCT (Fig. 1A), and in some, TREC numbers and TCR Vβ repertoire achieved pre-transplant values by 9 months post-HCT. Fifteen patients developed viremia with CMV (n=7), EBV (n=6), adenovirus (n=5), or HHV-6 (n=5); however, only two developed serious viral disease.  The incidence of acute GVHD was low, with 7 patients developing grade II-IV acute GVHD, and only 1 developing grade III-IV acute GVHD (Fig. 1B). All patients responded to therapy. None of the 24 patients who are beyond Day 180 post-UCBT have developed extensive chronic GVHD. 13 of 18 patients evaluable at 1 year post-HCT are completely off systemic immunosuppression, and 12 of 18 no longer require IgG supplementation. Two patients died after day +100 post-transplant, one from cardiopulmonary complications of viruses acquired pre-transplant (CMV, adenovirus, and parainfluenza), and one from disease progression.  Twenty-six patients (92%) are alive with a median follow-up of 22 months (range 1.5-47 months) (Fig. 1C).

In conclusion, this novel RIC regimen allows for rapid engraftment of donor cells and immune reconstitution in chemotherapy-naive patients with acceptable rates of viral reactivation and GVHD despite the use of single-unit UCB grafts in most cases.  High rates of survival and improved quality of life was associated with a low incidence of end-organ toxicity and absence of extensive cGVHD.

Table.

Characteristic		N=28
Age (years) - median (range)		1.6 (0.5-33.0)
Gender - no. (%)	Male	12 (43%)
Diagnosis - no. (%)	Krabbe	7 (25%)
	Metachromatic Leukodystrophy	5 (18%)
	MHC II Deficiency	2 (7%)
	Diamond-Blackfan Anemia	2 (7%)
	Cartilage-Hair Hypoplasia	1 (4%)
	Combined Immunodeficiency (CID)	1 (4%)
	CID with Intestinal Atresias	1 (4%)
	DiGeorge Syndrome	1 (4%)
	Gaucher Disease	1 (4%)
	HLH	1 (4%)
	Hunter Syndrome	1 (4%)
	Severe Congenital Neutropenia	1 (4%)
	Tay-Sachs Disease	1 (4%)
	X-linked Adrenoleukodystrophy	1 (4%)
	XLP2	1 (4%)
	Osteopetrosis	1 (4%)
Stem Cell Source	UCB	23 (82%)
	Marrow	5 (18%)
Cell dose (E+07; TNC/kg) - median (range)	UCB	10.2 (3.8-22.5)
	Marrow	31.4 (11.8-86.0)
Cell dose (E+05; CD34/kg) - median (range)	UCB	3.33 (1.55-9.00)
	Marrow	22.4 (44.2-91.4)
Match (UCB) - no. (%)	6/6	9 (39%)
	5/6	7 (30%)
	4/6	7 (30%)
Match (Marrow) - no. (%)	8/8	4 (80%)
	7/8	1 (20%)
ABO mismatch - no. (%)		19 (68%)
Neutrophil engraftment (days) - median (range)		14 (9-33)
Platelet >20K (days; N=24) - median (range)		35 (17-56)
Platelets >50K (days; N=25) - median (range)		37 (18-105)

Figure 1