Partially matched related donor peripheral blood progenitor cell transplantation in paediatric patients adding fludarabine and anti-lymphocyte gamma-globulin

Abstract

Summary:Twenty-one paediatric patients (11 males and 10 females) received a CD34-selected partially matched related donor transplant for malignant (16 cases) and non-malignant conditions (five cases). The average cell dose was 11.13 ؋ 10 6 /kg. Fifteen of 16 patients with malignant conditions and one with non-malignant disease received total body irradiation plus cyclophosphamide. Three of 5 patients with non-malignant conditions and one with leukaemia, received busulphan plus cyclophosphamide. One patient with Fanconi anaemia received 100 mg/kg of cyclophosphamide. Fludarabine (25 mg/m 2 /day for 5 days) was administered prior to all these regimens. Additionally, anti-lymphocyte gamma-globulin (12.5 mg/kg/day) was administered from day ؊2 to day +2. Three (15%) patients failed to achieve complete chimaerism (CC). These patients received a second cell infusion. Two of them achieved CC. In the third patient, the percentage of donor cells was increased. The likelihood for engraftment was not related to the cell dose received. Acute graft-versus-host disease (GVHD) occurred in nine patients but only one developed GVHD Ͼgrade II. Eight patients developed active viral infections, which resolved after treatment. Patients receiving cell doses higher than our average had a significantly faster CD3 and CD4 cell recovery and experienced a lower incidence of viral infections. After 480 ؎ 255 days of median follow-up, 16/21 patients are alive and well and have CC. Three patients died of leukaemic relapse and a fourth from progression of his disease (adreno-leuko-dystrophy). We conclude that partially matched related donors are a feasible source of haemopoietic progenitor cells for transplantation for patients without matched familial or unrelated donors.

Haploidentical SCT in children: an update and future perspectives

“…34 The risk of acute and chronic GVHD was significantly reduced by all mentioned graft manipulation procedures and therefore comparable with that after matched unrelated donor transplantations. The rates ranged between 0-24% (acute GVHDXgrade II) and between 0-19% (chronic) 5,9,11,13,35,40 after CD34 or CD133 positive selection and between 36 and 27% (acute GVHDXgrade II) after CD3 depletion and CD20 or CD19 depletion. 7,14 In contrast to those studies, Chinese and Japanese groups investigated the use of G-CSF primed BM/PBSC without any in vitro T cell depletion on the basis of antithymocyte globulin and post-transplant immunosuppression with 3-4 agents.…”

“…29 High median stem cell doses between 11.3 and 24.3 Â 10 6 /kg were infused in several studies according to the megadose concept of Reisner et al 16 To date, there is no clear clinical evidence for the optimum cell dose, and a wide range of CD34 þ selected progenitors (4.2-58 Â 10 6 /kg) was able to induce successful engraftment. 5,9,11,13,18,34 In patients with T and B cell-depleted grafts, cell doses of approximately 2 Â 10 6 /kg resulted in stable engraftment. Frequent analyses of T cell chimerism can help to predict graft rejection, either by PCR analysis of VNTR regions or by flow cytometry of lymphocyte subsets with MoAb against HLA Ags of recipient and donor.…”

“…17 The low incidence of EBV-associated lymphoproliferative disease in pediatric patients with CD34 þ or CD133 þ selected grafts was related to the additional indirect depletion of mature B cells harboring the EBV. 5,9,11,13,18 However, new stem cell markers, targeting CD34 negative progenitors, have questioned whether positive selection procedures will be sufficient to identify early and pluripotent progenitor cells. 7 Further, other immune components such as natural killer (NK) cells, DCs and monocytes are lost during the separation procedure and cannot be used to generate antitumor, antiviral or graft-facilitating effects.…”

“…9,10,11,13,46 ADV has become the most common viral pathogen, with cumulative risks of infection between 8.5 and 29% and infectious deaths between 0 and 17%. 9,13,47 Feuchtinger et al 47 demonstrated that all patients with ADV-associated mortality had no specific T cells, whereas survivors of ADV infections developed a specific T cell immunity against adenoviral Ags. Similar observations in CMV infections underline the potential role of Ag-specific T cells as a sufficient antiviral defense.…”

“…32 To overcome the HLA barrier, most conditioning regimens for haplotransplantation in children were myeloablative and BU or TBI (14.4 or 12 Gy) based. 2,3,5,9,11,13,18 Thiotepa was added by some groups to enhance myeloablation. 12 Alternatively, VP16 was used in patients with acute leukemias.…”