Intensive postgrafting immune suppression combined with nonmyeloablative conditioning for transplantation of HLA-identical hematopoietic cell grafts: results of a pilot study for treatment of primary immunodeficiency disorders

Abstract

This study was designed to determine the safety of a nonmyeloablative regimen in patients with primary immunodeficiency disorders (PID) who had infections, organ dysfunction or other risk factors that precluded conventional hematopoietic cell (HC) transplant. Fourteen patients received HLA-matched related (n ¼ 6) or unrelated (n ¼ 8) HC grafts from marrow (n ¼ 8), peripheral blood mononuclear cells (n ¼ 5) or umbilical cord blood (n ¼ 1), either without conditioning (n ¼ 1), or after 200 cGy total body irradiation alone (n ¼ 3) or with 90 mg/m 2 fludarabine (n ¼ 10). All patients were given postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. Mixed (n ¼ 5) or full (n ¼ 8) donor chimerism was established in 13 patients, and one patient rejected the graft. Eight patients developed acute grade III (n ¼ 1) and/or extensive chronic GVHD (n ¼ 8). With a median follow-up of 4.9 (range, 0.7-8.1) years, the 3-year overall survival, event-free survival and transplant-related mortality were 62, 62 and 23%, respectively. Correction of immune dysfunction was documented in 8 of 10 patients with stable donor engraftment. These preliminary results indicated that this approach was associated with stable donor engraftment and a low incidence of early mortality and, thus, can be considered for certain high-risk patients with PID. However, there was a risk of GVHD, which is an undesirable outcome for this group of patients.

Increasing mixed chimerism and the risk of graft loss in children undergoing allogeneic hematopoietic stem cell transplantation for non-malignant disorders

“…For example, while most children with primary immunodeficiency disorders such as SCID develop normal immune function with a low level of donor chimerism, some children with Wiskott-Aldrich syndrome may require CDC to control symptoms of autoimmunity. 22,23 The incidence of increasing MC was 33% in our study which is within the range of published results. Hoelle et al 4 reported an incidence of 13% in a cohort of children with severe aplastic anemia receiving CD34 þ enriched transplants, and Willasch et al 11 reported a 34% incidence of increasing MC in children with non-malignancies conditioned with busulfan, cyclophosphamide and antithymocyte globulin, 70% of whom received T-cell depleted transplants.…”

Reduced Intensity Transplantation for Primary Immunodeficiency Disorders

“…15 The majority of patients received 200 cGy TBI plus Flu (30 mg/m 2 per day; x3 days -4 to -2) as conditioning and all patients received HLA-matched grafts with intensive post-graft immunosuppression with CsA/MMF. No serotherapy was given.…”

“…19 Following RIT, the use of PBSCs appears to be associated with improved donor chimerism in recipents with PID, 14,15 but at the cost of increased rates of GvHD, particularly in mMUD; in London PBPCs are advocated for 10/10 HLA matched related and unrelated donors following RIT HCT and new approaches are being pursued for mMUDs (Rao et al, 2010 manuscript in preparation). In the UK, the use of GCSF is not advocated in sibling donors <16 yrs of age, and as the combination of RIT and MSD BM often leads to low level donor chimerism in PID patients, MAC is generally preferred for this group.…”

Reduced intensity conditioning and allogeneic stem cell transplantation in childhood malignant and nonmalignant diseases

“…16 The majority of patients received 200 cGy TBI plus FLU (30 mg/m 2 per day; days À4 to À2) as conditioning and all patients received HLA-matched grafts with intensive post-graft immunosuppression with CsA/MMF. Thirteen patients established mixed (n ¼ 5) or full (n ¼ 8) donor chimerism and one rejected the graft.…”