Results of Haploidentical Stem Cell Transplantation after a Conditioning Regimen without Total Body Irradiation in Elderly Patients with Advanced Myeloid and Lymphoid Malignancies.
Authors: Selleslag Dominik L.D. , Hidajat Melanny , Van Droogenbroeck Jan , Van Hoof Achiel , Billiet Johan , Dehenau Dimitri , Nollet Friedel , Criel Arnold 
Published: October 2019

Abstract
Experience with haploidentical stem cell transplantation in elderly patients after non TBI (total body irradiation) containing regimens is limited. We report a single centre experience with haploidentical stem cell transplantation in 16 patients with poor prognosis myeloid and lymphoid malignancies refractory to conventional therapy or relapsing after autologous stem cell transplantation. For none of these patients a HLA matched related or unrelated donor was available. All patients were transplanted between April 2004 and May 2007. Age was between 16 and 71 yrs (median 57 yrs), 11 of 16 were more than 50 yrs old. Of the 16 patients 3 had lymphoid malignancies (1 Hodgkin, 1 myeloma, 1 Phi+ ALL) and 13 had high risk MDS (myelodysplasia) or primary or secondary AML. All patients had relapsed after or were refractory to conventional chemotherapy (11 patients) or had relapsed after autologous stem cell transplantation (5 patients). All patients were prepared with a conditioning regimen consisting of Thiotepa 2 × 5 mg/kg on day −8, ATG Fresenius 5 mg/kg on days −7 to −3, Fludarabine 40 mg/m2 on days −7 to −3, Melphalan 100–140 mg/m2 on days −2. CD34 selection was by Clinimacs without postgrafting GVHD prophylaxis. Grafts contained a median of 9,8 × 106 CD34/kg (range 3,3–16,6 × 106/kg) and a median of 0,11 × 105 CD3/kg (range 0,04–0,3 × 105/kg). All donors were haploidentical family members. 13 of 16 donor-recipient pairs had at least one KIR ligand mismatch in the GVH (graft versus host) direction. Graft rejection occurred in 2 of 16 transplants, 1 patient was rescued with a second transplant from another haploidentical donor. All surviving patients are full chimeras (> 95% donor chimerism). Median time to ANC > 0.5 x10 9/l was 12,5 days (range 7–18 days) and median time to platelets > 50 × 109/l was 21,5 days (range 14–199 days). 5 of 16 patients died before they achieved a platelet count > 50 × 109/l. Non relapse mortality occurred in 4 of 16 (25%) patients within 1 year after transplantation. Causes of death were: aspergillosis 1, VOD 1, CNS bleeding 1, cGVHD 1. Acute GVHD grade II-IV occurred in 3 patients and was manageable with steroids and/or ATG. Chronic GVHD was observed in 3 patients (after DLI in 2 of them). Infections were the most important complication: aspergillosis in 7 patients, CMV in 4 patients, listeria meningitis in 1 patient. EBV-associated lymphoproliferative disease was seen in 2 patients, both responded to rituximab and DLI (donor lymphocyte infusions). Disease progression and relapse occurred in 6 patients within 1 year after transplantation (myeloma 1, AML 5). None of the relapsing patients responded to escalating doses of DLI. At the time of this report 8 of 16 patients are surviving, 6 of them without evidence of disease between 159 and 1214 days (median 425 days) after transplantation. Of the 6 disease free survivors 4 are older than 50 yrs and 5 have a KIR ligand mismatch in the GVH direction. Kaplan Meier estimate for overall survival and disease free survival is 43% at 2 yrs and 39% at 2 yrs respectively. We conclude that transplantation from natural killer (NK) alloreactive haploidentical family donors offers potential cure to about one third of elderly patients with advanced leukemia or MDS considered incurable by other therapies. TBI does not seem to be required to benefit from this treatment approach. Relapse rate and infectious morbidity remain major obstacles.