Reduced Intensity Conditioning In Children Undergoing Unrelated Umbilical Cord Blood Transplantation for Non-Malignant Diseases: Preliminary Results Demonstrate a High Rate of Engraftment and Low Incidence of Gvhd
Authors: Parikh Suhag H , Martin Paul L , Driscoll Timothy A , Baker Jennifer , Piersol Ketti , Moffet Jerelyn , Stokhuyzen Andre , Kurtzberg Joanne , Szabolcs Paul 
Published: October 2019

Abstract
Abstract 3535

Background and Objective:
Reduced intensity conditioning (RIC) regimens decrease transplant related morbidity and mortality and are increasingly being utilized prior to allogeneic hematopoietic stem cell transplantation. Unrelated umbilical cord blood transplantation (UCBT) has been successful with RIC regimens for patients with various malignancies, who have undergone multiple cycles of chemotherapy, thereby reducing the likelihood of graft rejection. However, for treatment of non-malignant diseases where co-morbid conditions would warrant reduced toxicity, previously reported successful RIC regimens utilizing UCBT have failed to provide reproducible engraftment commonly resulting in graft rejection and autologous reconstitution. We designed a novel RIC regimen for this group of patients with the main objective of studying its efficacy to promote clinically significant and durable engraftment after UCBT.

Methods:
Between December 2008 and July 2010, eight children with non-malignant diseases lacking matched related donors enrolled on this protocol (clinicaltrials.gov NCT00744692): MPS I (1), MPS IIIB (2), Metachromatic leukodystrophy (MLD) (1), Cartilage Hair Hypoplasia (CHH) (1), Zap-70 deficiency (1), and Hemophagocytic lymphohistiocytosis (HLH) (2). Seven children, with >42 days follow-up post-UCBT are presented in this preliminary interim analysis. Immunosuppression was based on alemtuzumab (3.2mg/kg) and fludarabine (150 mg/m2), while melphalan (140 mg/m2), thiotepa (200mg/m2) and hydroxyurea (days -22 to -10) provided myelosuppression. GVHD prophylaxis consisted of tacrolimus and MMF. G-CSF support was provided to all patients by day +1. Median age and weight at the time of transplant were 3.3 years and 15.1 kg respectively. Male: Female ratio was 1.3. All patients received single UCBT with a cryopreserved median cell dose of 7.7 × 107 TNC/kg (range 5.7–29.3). HLA matching was 4/6, 5/6 and 6/6 in 1, 4 and 2 patients respectively.

Results:
Prior to enrollment, the MPS I patient had significant cardiomyopathy with obstructive sleep apnea and the child with ZAP-70 deficiency had severe bronchiectasis and enteroviral meningitis. Nevertheless, all patients tolerated the conditioning regimen well. None of the patients had mucositis > grade 2, although all required TPN and narcotic support. To date, no patient experienced CNS, cardiac, pulmonary or hepatorenal toxicity attributable to conditioning, and no one had VOD. One patient (CHH with 6/6–matched UCBT demonstrating no post-thaw growth in colony forming assay) experienced autologous recovery on day +30. He was successfully retransplanted with RIC conditioning. The remaining patients (6 of 7) engrafted at a median of 20 days post-transplant (range 15–28 days). At the time of last evaluation, whole blood donor chimerism in engrafted patients ranged from 63% to >98%. Acute GVHD of skin, Grade 1, was seen in 4 patients. None of the patients have had Grade 2–4 acute GVHD or chronic GVHD thus far, although follow-up for chronic GVHD is short. Platelet count > 50K, untransfused, was achieved in 5 of 6 engrafted patients at a median of 39 days. Viral reactivation and/or de novo viral infections were seen commonly, majority without appreciable end organ disease. Adenovirus infection was noted in 4 patients (2 patients had adenoviral gastroenteritis and 1 patient had detection of adenovirus in nasal wash that resolved without specific systemic therapy; 1 patient had adenoviremia that resolved with cidofovir and adoptive immunotherapy); the patient with autologous recovery had prolonged CMV viremia. Two patients with immune deficiencies had pre-existing infectious histories, but no worsening was noted after transplant.
Six of 7 patients are alive with a median follow-up of 256 days (43 – 587 days). One patient with mixed chimerism died on day +170 of an acute hemolytic transfusion reaction. Five of 7 patients survive event free.

Conclusion:
Reduced intensity conditioning consisting of alemtuzumab, fludarabine, melphalan, thiotepa and hydroxyurea is well tolerated and results in a high rate of donor engraftment with a low risk of GVHD in children with non-malignant diseases undergoing UCBT. Despite the common occurrence of viral infections these have not caused severe end organ damage or death. Long-term follow-up will determine whether donor chimerism will be durable after this approach.

Disclosures:
No relevant conflicts of interest to declare.