Abstract
Myeloablative conditioning regimens may cause life threatening transplant related toxicities in patients with Primary Immune Deficiency Disorders (PIDD), particularly in patients with co-morbid conditions. Previously we reported the outcomes of a phase I study using nonmyeloablative conditioning in 14 high-risk patients with PIDD and observed 3-year survival and transplant related mortality (TRM) of 62% and 23%, respectively. Although encouraging, the incidence of chronic GVHD was 47% at 1 year, which is an undesirable outcome for patients with nonmalignant diseases. We reasoned that the incidence of GVHD might be reduced by replacing PBSC with marrow; however, our previous experience showed marrow to be associated with a higher risk of graft rejection. Therefore our standard nonmyeloablative regimen of 90 mg/m2 fludarabine and 2 Gy total body irradiation (TBI) was slightly intensified to include either Alemtuzumab, or, if Alemtuzumab was contraindicated, an additional 2 Gy TBI. Twenty-three patients with PIDD and significant underlying serious infections and/or organ dysfunction (table 1) were given HLA-matched related (n = 10) or unrelated (n = 13) marrow grafts following nonmyeloablative conditioning modified with either Alemtuzumab (n = 3) or 4 Gy TBI (n = 20). All patients received mycophenolate mofetil and cyclosporine for postgrafting immunosuppression. Of the 20 patients evaluable, 18 had mixed (6-49%, n = 1; 50-94%; n = 10) or full (> 95%; n = 7) donor CD3+ T-cell chimerism. Two patients had graft rejection and survive disease-free following 2nd successful transplantation. The 2-year cumulative incidence of chronic GVHD was 22%. With a median follow-up of 26.8 months, the 2-year survival was 76% and the day 200 and 2-year TRM were 14% and 24%, respectively. Four patients died of pre-existing infections and/or organ dysfunction and one patient died of GVHD. Six patients were not evaluable for disease response due to short follow-up (n = 1), 2nd HCT (n = 2), or early death (n = 3). Fifteen patients had improvement in, or correction of, their underlying PIDD. Although these results are preliminary, our early experience suggests that outcomes can be improved in high-risk patients with PIDD by using a modified nonmyeloablative conditioning regimen and by selecting marrow as the source of hematopoietic cells. We observed stable donor engraftment in most cases, an acceptable TRM, a low incidence of chronic GVHD, and correction of underlying disease processes.Table 1Pre-transplant risk factors and survival among 23 patients who received nonmyeloablative conditioning followed by allogeneic marrow grafts for high-risk PIDDPatient #DiagnosisAge (yr)/GenderPre-transplant Risk FactorsSurvival (months)1SCID1.4/FParainfluenza, Rhinovirus, PCP, FTT>48.72X-SCID0.5/MCMV reactivation>45.13X-SCID0.8/MAdenovirus, PCP, FTT>36.04SCID1.9/MDisseminated CMV disease with pneumonitis, myocarditis, nephritis, and hepatitis, FTT>27.85SCID1.2/FDisseminated CMV disease with pneumonitis, adenovirus pneumonitis, PCP, FTT†Day +16SCID0.9/MPCP, Influenza B, Rhinovirus, FTT†7.57SCID1.0/FDisseminated adenovirus with hepatitis, FTT†Day +158SCID0.4/MParvovirus, FTT>Day +49Complete DiGeorge0.4/MSeizures, FTT>23.710CID9.8/FCMV reactivation, chronic lung disease, h/o fulminant hepatic failure with hyperammonemia and encephalopathy, h/o acute renal failure with persistent renal tubular acidosis, polyarticular arthritis, Moraxella catarrhalis sinusitis and pneumonia, FTT>27.611CID0.7/FEnterovirus pneumonia (mechanical ventilation dependent before and at time of HCT)†1.412CID2.9/MBronchitis, recurrent pneumonia>2.313CVID24.7/FCMV reactivation, Candida pneumonia, lymphocytic interstitial pneumonitis, liver disease with portal HTN of unknown etiology s/p TIPS procedure, IDDM>11.114CGD26.5/MPulmonary Scopulariopsis, FTT>26.915CGD10.7/MInvasive pulmonary Aspergillosis, Protein losing enteropathy>15.016IPEX16.9/MEBV LPD of the lungs & gut, chronic interstitial lung disease, IDDM>26.017CHH2.9/FEnterovirus, Norovirus, Hirschsprung’s disease s/p total colectomy, TPN dependent, FTT>4.318CHH8.7/FCMV reactivation, chronic lung disease, hemolytic anemia>4.319HLH2.7/MPneumonia, h/o multi-system organ failure - shock, renal failure – dialysis dependent at HCT†7.420Congenital Neutropenia3.5/MPrimary EBV infection>45.121HLH0.6/FHLH>43.422ADA-SCID0.7/MRecurrent viral pneumonias, FTT>42.023CD40LD11.3/MCD40LD, s/p colectomy due to pre HCT dysplasia throughout colon>35.7CD40LD= CD40 ligand deficiency; CGD=chronic granulomatous disease; CHH=cartilage hair hypoplasia; CMV=cytomegalovirus; CVID=common variable immunodeficiency; EBV-LPD=Epstein-Barr virus lymphoproliferative disease; FTT=failure to thrive; IDDM=insulin dependent diabetes mellitus; HLH= hemophagocytic lymphohistiocytosis; h/o=history of; HTN=hypertension; IPEX=immune dysregulation-polyendocrinopathy-enteropathy-X–linked; PCP=pneumocystis carnii pneumonia; (S)CID=(severe) combined immune deficiency; s/p=status post; TIPS=transjugular intrahepatic portosystemic shunt, yr=year. Patients 21, 22 and 23 received Alemtuzumab as part of the conditioning regimen.> Alive; †Dead; #Number Open table in a new tab CD40LD= CD40 ligand deficiency; CGD=chronic granulomatous disease; CHH=cartilage hair hypoplasia; CMV=cytomegalovirus; CVID=common variable immunodeficiency; EBV-LPD=Epstein-Barr virus lymphoproliferative disease; FTT=failure to thrive; IDDM=insulin dependent diabetes mellitus; HLH= hemophagocytic lymphohistiocytosis; h/o=history of; HTN=hypertension; IPEX=immune dysregulation-polyendocrinopathy-enteropathy-X–linked; PCP=pneumocystis carnii pneumonia; (S)CID=(severe) combined immune deficiency; s/p=status post; TIPS=transjugular intrahepatic portosystemic shunt, yr=year. Patients 21, 22 and 23 received Alemtuzumab as part of the conditioning regimen.> Alive; †Dead; #Number