title: Escalated lymphodepletion followed by donor lymphocyte infusion can induce a graft-versus-host response without overwhelming toxicity.
abstract: Treatment of relapse of hematological malignancies following allogeneic hematopoietic SCT (allo-HSCT) remains very challenging and relies usually on the readministration of chemotherapy combined with donor lymphocyte infusion (DLI). To enhance DLI effectiveness, lymphodepletion (LD) with fludarabine (Flu) and/or CY before the injection of lymphocytes is an attractive modality to modify the immune environment, leading possibly to suppression of regulatory T cells (T(reg)) and exposing the patient to cytokine activation. However, LD before DLI may lead to induction of deleterious GVHD. To avoid inducing overwhelming toxicity, we proceeded by escalating doses of both LD and DLI. Eighteen patients with various non-CML hematological malignancies who relapsed following allo-HSCT were treated with chemotherapy and LD-DLI or LD-DLI upfront. T-cell subpopulation and DC levels as well as cytokine plasma levels (IL-7, IL-15) were measured before and following LD-DLI. Cumulative incidence of acute grade II-IV GVHD was 29.4% similar to that reported in patients receiving DLI without LD. In addition, Flu alone with low dose of DLI was not associated with severe GHVD. CY/Flu at the respective doses of 600 mg/m(2) on day 1 and Flu 25 mg/m(2)/day on days 1-3 did not result in a marked decrease of T(reg) cells, nor in endogenous IL-7 and IL-15 production. However, a peripheral expansion of DCs was observed. These findings suggest that the escalated dose procedure appears safe and prevent overwhelming toxicity. A dose-limiting toxicity has not yet been reached.
authors: Centre Hospitalier et Universitaire (CHU) de Nantes, Hématologie Clinique, 1 Place Ricordeau, Nantes, France. thierry.guillaume@chu-nantes.fr
authors: T
authors: T
authors: Guillaume
authors: B
authors: B
authors: Gaugler
authors: P
authors: P
authors: Chevallier
authors: J
authors: J
authors: Delaunay
authors: S
authors: S
authors: Ayari
authors: A
authors: A
authors: Clavert
authors: F
authors: F
authors: Rialland
authors: S
authors: S
authors: Le Gouill
authors: N
authors: N
authors: Blin
authors: T
authors: T
authors: Gastinne
authors: B
authors: B
authors: Mahé
authors: V
authors: V
authors: Dubruille
authors: P
authors: P
authors: Moreau
authors: M
authors: M
authors: Mohty
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006086:Graft vs Host Disease / Q000097:blood / Q000453:epidemiology / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000097:blood / Q000453:epidemiology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015994:Incidence; D015848:Interleukin-5 / Q000097:blood; D015851:Interleukin-7 / Q000097:blood; D019520:Living Donors; D008212:Lymphocyte Depletion / Q000379:methods*; D017710:Lymphocyte Transfusion / Q000379:methods*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011446:Prospective Studies; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: C508599:IL5 protein, human; C508605:IL7 protein, human; D015848:Interleukin-5; D015851:Interleukin-7