Reduced Intensity Conditioning (RIC) and Hematopoietic Stem Cell Transpalntation (HSCT) Utilizing Extracorporeal Photopheresis (ECP), Fludarabine, and Targeted Dose Busulfan in Children.
Authors: Schneiderman Jennifer , Duerst Reggie , Campbell Kim , Krutsick Amy , Tse William , Thormann Kimberly , Kletzel Morris , Jacobsohn David A. 
Published: October 2019

Abstract
RIC for HSCT has been used to treat a variety of diseases in adults. Acute and chronic graft vs host disease (GVHD) continue to cause morbidity and mortality. ECP is an immunomodulatory cell therapy being investigated as treatment for various immune-mediated disorders, including GVHD. ECP is an established therapy for chronic GVHD, but has not been routinely used as prophylaxis. We hypothesized that combining ECP with RIC prior to HSCT would reduce the incidence of GVHD and 100-day transplant related mortality (TRM) without affecting time to engraftment. Eight children have been enrolled; ranging in age from 10 – 16 years (mean 13.6), with CML (n=2), severe aplastic anemia (SAA) (n=3), ALL in CR2 (n=1), or relapsed Hodgkin’s disease after autologous transplant (n=2). Stem cell sources included peripheral blood from matched related (n=6), mis-matched related (n=1), and matched unrelated (n=1) donors. Conditioning consisted of 2 weekly treatments of ECP (treatment=2 consecutive days) beginning two weeks prior to transplant, followed by fludarabine (days -6 to -2) and targeted dose busulfan to reach a daily AUC of 4000 μmol*min (days -5, -4); GVHD prophylaxis was: mycophenolate mofetil (MMF), cyclosporine, and weekly treatments of ECP starting once leukocyte chimerism reached 50% through day +100. Full engraftment (>95% total donor chimerism) was achieved by day 12 – 81 (median 29 days) in all patients. Two patients required immune modulation for falling chimerism; one responded to removal of immune supression, the other required donor lymphocyte infusion (DLI). Both subsequently developed grade 3 aGVHD. Patients with CML and SAA are fully engrafted and in remission. Four had central line infections, one had adenovirus antigenemia, and all 5 at risk for CMV had reactivation. They underwent pre-emptive treatment without development of disease. ECP was well tolerated. There were no toxic deaths, episodes of veno-occlusive disease or mucositis; none required parenteral nutrition. Patients were admitted to the hospital for 2 days during the preparative regimen (IV busulfan); between day 0 and 100 patients were admitted for a median of 11 days (range 0 – 25). We conclude that in children using ECP as part of RIC and GVHD prevention is feasible, time to engraftment is acceptable, and complications are minimal as evidenced by short inpatient stays. However, immune supression appears to be excessive, given the rates of CMV reactivation and the declining chimerism of two patients while on ECP. ECP appears to be effective in preventing aGVHD, as the only patients who developed aGVHD were those requiring immune modulation.
Patient Characteristics Patient # Diagnosis Donor Chimerism > 50% (days) Chimerism > 95% (days) aGVHD cGVHD Disease Status *Interventions due to falling chimerism 1 CML Matched Sib 13 29 None None NED following DLI & Imatinib for rising BCR/ABL, Day +384 2 SAA Matched Sib 8 26 None Extensive NED, Day +328 3 CML Matched Sib 26 63 (following DLI)* Grade 3 Extensive NED, Day +278 4 SAA Mismatched Related 12 81 (following removal of immune supression)* Grade 3 Limited NED, Day +222 5 ALL (CR2) Matched Sib 12 28 None None Relapse, Day +100 6 HD (CR3) MUD 20 33 None None Relapse, Day +100 7 SAA Matched Sib 7 12 None None NED, Day +125 8 HD (CR2) Matched Sib 28 47 None N/A NED, Day +62