title: Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: an update.
abstract: Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with CD34-selected stem cells has been complicated by high regimen related toxicities, slow engraftment and delayed immune reconstitution leading to increased treatment related mortality (TRM). A new regimen using reduced intensity conditioning (RIC) and graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads on a CliniMACS device may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, natural killer, graft facilitating and dendritic cells. RIC was performed with fludarabine (150-200 mg/m(2)), thiotepa (10 mg/kg), melphalan (120 mg/m(2)) and OKT-3 (5 mg/day, day -5 to +14) and no posttransplant immunosuppression. Twenty nine patients (median age=42 (range, 21-59) years) have been transplanted with this regimen. Diagnosis were AML (n=16), ALL (n=7), NHL (n=3), MM (n=2) and CML (n=1). Patients were "high risk" with refractory disease or relapse after preceding HCT. The CD3/CD19 depleted haploidentical grafts contained a median of 7.6x10(6) (range, 3.4-17x10(6)) CD34+ cells/kg, 4.4x10(4) (range, 0.006-44x10(4)) CD3+ T cells/kg and 7.2x10(7) (range, 0.02-37.3x10(7)) CD56+ cells/kg. Donor-recipient KIR-ligand-mismatch was found in 19 of 29 patients. The regimen was well tolerated with maximum acute toxicity being grade 2-3 mucositis. Because of severe neurotoxicity in 4 patients treated with 200 mg/m(2) fludarabine, the dose was reduced to 150 mg/m(2). Engraftment was rapid with a median time to >500 granulocytes/microL of 12 (range, 10-21) days, >20,000 platelets/microL of 11 (range, 7-38) days and full donor chimerism after 2-4 weeks in all patients. Incidence of grade II-IV degrees GVHD was 48% with grade II degrees =10, III degrees =2 and IV degrees =2. One patient, who received the highest T-cell dose, developed lethal grade IV GVHD. TRM in the first 100 days was 6/29 (20%) with deaths due to idiopathic pneumonia syndrome (n=1), mucormycosis (n=1), pneumonia (n=3) or GVHD (n=1). Overall survival is 9/29 patients (31%) with deaths due to infections (n=7), GVHD (n=1) and relapse (n=12) with a median follow-up of 241 days (range, 112-1271). In conclusion, this regimen is promising in high risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing.
authors.affiliation: Medical Center, University of Tübingen, Hematology/Oncology Otfried-Mueller Str. 1072076 Tuebingen, Germany. wolfgang.bethge@med.uni-tuebingen.de
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Bethge
authors.forename: Christoph
authors.initials: C
authors.lastname: Faul
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.forename: Gernot
authors.initials: G
authors.lastname: Stuhler
authors.forename: Dietrich W
authors.initials: DW
authors.lastname: Beelen
authors.forename: Peter
authors.initials: P
authors.lastname: Lang
authors.forename: Matthias
authors.initials: M
authors.lastname: Stelljes
authors.forename: Wichard
authors.initials: W
authors.lastname: Vogel
authors.forename: Matthias
authors.initials: M
authors.lastname: Hägele
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
mesh_terms: D000328:Adult; D018941:Antigens, CD19; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017252:CD3 Complex; D002423:Cause of Death; D002469:Cell Separation / Q000379:methods; D006086:Graft vs Host Disease; D006239:Haplotypes; D019337:Hematologic Neoplasms / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods* / Q000401:mortality; D006648:Histocompatibility; D006801:Humans; D008212:Lymphocyte Depletion / Q000379:methods*; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D016853:Muromonab-CD3 / Q000008:administration & dosage; D015996:Survival Rate; D013852:Thiotepa / Q000008:administration & dosage; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity
chemical_list: D018941:Antigens, CD19; D017252:CD3 Complex; D016853:Muromonab-CD3; D013852:Thiotepa; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan