title: Phase II study of CD4+-guided pentostatin lymphodepletion and pharmacokinetically targeted busulfan as conditioning for hematopoietic cell allografting.
abstract: One limitation of reduced-intensity preparative regimens is potential for graft failure. We have developed a regimen that targets CD4(+) lymphodepletion to ensure early and durable engraftment. The primary endpoint was achievement of ≥50% CD3(+) donor chimerism by day +28. Forty-two patients (median age, 53 years; range, 29 to 73 years) received pentostatin 4 mg/m(2) i.v. on days -28, -21, and -14 when the CD4(+) cell count was >100 cells/μL and on days -4 and -3 regardless of CD4(+) level. Rituximab 375 mg/m(2) was administered to patients with CD20(+) malignancies on days -21, -14, -7, +1, and +8. Busulfan 200 mg/m(2) i.v. was administered on days -4 and -2 at a dose to target a cumulative AUC dose of 16,000 (±10%) μmol·min/L. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus methotrexate in 86% of patients. Donors were matched-related (47%), matched unrelated (43%), or mismatched unrelated (10%). Chronic lymphocytic leukemia (45%) and follicular non-Hodgkin lymphoma (14%) were the most common diagnoses. Disease status at initiation of the preparative regimen was complete remission in 22%, partial response in 55%, and stable/progression in 24%. The median percent CD4(+) cell count decrease from baseline (day -28) was 52% to day -21, 66% to day -14, 62% to day -7, and 91% to day 0. At day +28, all 42 patients (100%) had ≥50% CD3(+) donor chimerism. No patient experienced graft failure. Overall response rate was 82% (complete remisson, 67%). The day +100 cumulative incidence of grade II-IV acute GVHD was 59% (grade III-IV acute GVHD, 19%), and the 2 year cumulative incidence of chronic GVHD was 69% (moderate/severe, 58%). Nonrelapse mortality was 2% at day +100 and 17% at 2 years. Two-year PFS was 55%, and OS was 68%. This regimen ensures durable engraftment, is effective against persistent disease, and results in relatively low mortality from causes other than relapse.
authors: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL 33612, USA. Mohamed.Kharfan-Dabaja@MOFFITT.org
authors: Mohamed A
authors: MA
authors: Kharfan-Dabaja
authors: Claudio
authors: C
authors: Anasetti
authors: Hugo F
authors: HF
authors: Fernandez
authors: Janelle
authors: J
authors: Perkins
authors: Jose L
authors: JL
authors: Ochoa-Bayona
authors: Joseph
authors: J
authors: Pidala
authors: Lia E
authors: LE
authors: Perez
authors: Ernesto
authors: E
authors: Ayala
authors: Teresa
authors: T
authors: Field
authors: Melissa
authors: M
authors: Alsina
authors: Taiga
authors: T
authors: Nishihori
authors: Frederick
authors: F
authors: Locke
authors: Javier
authors: J
authors: Pinilla-Ibarz
authors: Marcie
authors: M
authors: Tomblyn
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002066:Busulfan / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D002908:Chronic Disease; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D015649:Pentostatin / Q000627:therapeutic use*; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D000970:Antineoplastic Agents; D015649:Pentostatin; D002066:Busulfan
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