Reduced Intensity Conditioning Regimen Combined with Single Unit Cord Blood Transplantation Is Effective and Safe for Children with Inherited Metabolic Disorders and Combined Immunodeficiency Diseases

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/mortality secondary to infections following intense serotherapy. Here we report on a novel RIC conditioning regimen for chemotherapy naïve children.

Between 2012 and 2013, 12 consecutive patients (median age 1 year, range: 0.5-14 years) underwent single unit umbilical cord blood transplantation (UCBT) at the Children's Hospital of Pittsburgh (Table). Patients received alemtuzumab (1.2-2.2 mg/kg), hydroxyurea (30 mg/kg/day), fludarabine (150 mg/m²), melphalan (140 mg/m²), and thiotepa (200 mg/m²), with tacrolimus and mycophenolate as GVHD prophylaxis. Most patients received an HLA-mismatched unit. The median cell dose was 8.6 x10⁷ (range: 3.8-11.0 x10⁷) TNC/kg and 2.55 x10⁵ (range 1.55-6.17 x10⁵) CD34+ cells/kg.

Neutrophil engraftment was rapid, and occurred in all patients at a median of 15.5 days post-UCBT (range: 12-31). Platelet engraftment (>50K) occurred at a median of 40.5 days post-UCBT (range 32-63). 11 of 12 patients had >98% donor whole blood chimerism at first measurement, performed at a median of 30 days post-UCBT. The median chimerism was 100% in whole blood (range: 89-100%) and T cell fraction (range 95-100%) at 6 months post-UCBT (n=7), and 96% (range: 85-100%) in whole blood and 91% (range 76-100%) in the T cell fraction at 12 months (n=5). In a limited sample of patients, TREC number and TCR Vβ repertoire achieved pre-transplant values by 9 months post-UCBT (Figure). 5 patients (42%) developed viremia with CMV (n=2), adenovirus (n=1), EBV (n=2), or HHV-6 (n=3); however, no patients developed end-organ disease. The incidence of acute GVHD was low, with 25% of patients developing grade II-IV acute GVHD, and only one with grade III acute GVHD. All patients responded to therapy. None of the 9 patients who are beyond Day 180 post-UCBT have developed extensive chronic GVHD. 5 of the 6 patients evaluable at 1 year post-UCBT are completely off systemic immunosuppression. All patients are alive with a median follow-up of 11 months (range 3-25 months).

In conclusion, this novel RIC regimen allows for rapid engraftment of donor cells and immune reconstitution with acceptable rates of viral reactivation and GVHD.

 

Table

 

Characteristics		N =12
Disease – N (%)	Krabbe Disease	3 (25%)
	MHC II Deficiency	2 (17%)
	Metachromatic Leukodystrophy	1 (8%)
	Hunter Syndrome	1 (8%)
	Diamond-Blackfan Anemia	1 (8%)
	Cartilage-Hair Hypoplasia	1 (8%)
	Combined Immunodeficiency	1 (8%)
	HLH	1 (8%)
	Osteopetrosis	1 (8%)
Donor Match – N (%)	6/6	5 (42%)
	5/6	3 (25%)
	4/6	4 (33%)
Acute GVHD - N (%)	Grade I	2 (17%)
	Grade II	2 (17%)
	Grade III-IV	1 (8%)
GVHD Target Organ - N (%)	Skin	4 (33%)
	GI	2 (17%)

Figure