Reconstitution of lymphocyte subpopulations in children with inherited metabolic storage diseases after haematopoietic cell transplantation

Abstract

Summary We prospectively evaluated the reconstitution of lymphocyte subpopulations in nine children with lysosomal diseases who underwent 11 allogeneic haematopoietic cell transplants (HCTs) following CD34+ immunomagnetic enrichment, limited T‐cell addback and in vivo B‐cell depletion. Absolute lymphocyte count recovery was slow to cross the 5th percentile, occurring at a median of 10 months after HCT in patients with full chimaerism. Natural killer cells represented up to 90% of the total lymphoid population during the first 3 months. CD4+ lymphocyte recovery occurred 9–18 months after HCT. In most patients, CD8+ lymphocyte recovery was slow and comparable with that of CD4+ lymphocytes. The CD4+/CD8+ ratio normalised by 3–7 months after HCT in 50% of the patients. CD8+ lymphocyte recovery was enhanced in patients with viral reactivation. Reconstitution of B‐lymphocytes was particularly delayed in patients treated with rituximab. Declining chimaerism, rejection and viral reactivation were the most common problems in our series. Because of the unique graft manipulation, the pace of lymphocyte reconstitution was particularly slow, suggesting that these patients are at a significantly increased risk of infections for up to 2 years after HCT.

In vivo B-cell depletion with rituximab for alternative donor hemopoietic SCT

“…10 We started our patients with lymphoid malignancies on rituximab 200 mg on day þ 5, and were favorably impressed with the initial results. 16 We have therefore used rituximab more systematically and it is now part of our standard of care, in patients undergoing an unrelated donor transplant, whether the stem cell source is marrow, blood or cord blood.…”

“…Only one child developed EBV-PTLD, and this was the only one who did not receive prophylactic rituximab, because of the lack of parental consent. 10 Following this encouraging experience, we started a pilot study with a fixed prophylactic dose of rituximab (200 mg) given on day þ 5 after an alternative donor transplant. We chose a lower dose as compared with the Monza report, as we had no evidence that the conventional 375 mg/m 2 was necessary, and we decided to move the infusion up to day þ 5 in order not to interfere with early cellular interactions after the infusion of donor cells.…”

“…10 In this study, children received CD34-selected grafts, ATG as GvHD prophylaxis and in vivo B-cell depletion with rituximab 375 mg/m 2 on day þ 1 after transplant to prevent EBV infection. Only one child developed EBV-PTLD, and this was the only one who did not receive prophylactic rituximab, because of the lack of parental consent.…”

Monoclonal antibodies and progressive multifocal leukoencephalopathy

“…73 The rate of B-cell reconstitution varies from 6 months to up to 24 months depending on additional anti-lymphocyte treatments, especially stem cell transplantation. 74,75 Therefore, PML following rituximab therapy develops in conjunction with the reconstitution of the B-cell population. Additionally, rituximab also have reduced CD3 T-cells in the cerebrospinal fluid.…”

Reply to “‘Thinking without thinking’ about natalizumab and PML”

“…Reconstitution of the peripheral B-cell population consists of immature B cells with delays especially in repopulation of memory cells [4]. The rate of B-cell reconstitution varies from 6 months to up to 24 months depending on additional antilymphocyte treatments, especially stem cell transplantation [5,6]. The observation of PML in the face of treatment with a monoclonal antibody that eradicates the B-cell population seems to controvert the hypothesis that JCV-infected B cells bring the infection to the brain.…”