Lineage‐specific engraftment and outcomes after T‐cell‐depleted peripheral blood stem cell transplant with Flu/Cy/TBI conditioning

Abstract

Allogeneic stem cell transplantation (SCT) continues to provide the best chance of cure for selected patients with haematological malignancies. However, transplant-related mortality (TRM) and graft-versus-host disease (GVHD) offset the unique therapeutic advantage of the graft-versus-leukaemia (GVL) effect. Although T-cell-depleted (TCD) SCT results in lower TRM and GVHD rates, the disease-free survival is comparable with that of unmanipulated SCT because of a higher rate of disease relapse and graft rejection (Marmont et al, 1991). To offset these disadvantages, while conserving the beneficial effect of T-cell depletion, we have used a myeloablative TCD peripheral blood stem cell transplant (PBSCT) followed by a transfusion of donor lymphocytes (DLI) after a delay of 45-100 d. The rationale of this approach was to boost T-cell immunity while mitigating GVHD with the delayed lymphocyte infusion (Barrett et al, 1998). Several studies have drawn attention to the frequent occurrence of mixed haematopoietic chimaerism after TCD transplants and have linked relapse and unfavourable transplant outcome with the mixed chimaeric state (Walker et al, 1986;Schaap et al, 1997;Bader et al, 1998;Barrios et al, 2003;Lamba et al, 2004). However, the relative patterns of engraftment of T-cells and myeloid cells have not been well described after these myeloablative SCT. We therefore evaluated donor T-cell and myeloid chimaerism in our hybrid T-cell depletion and add-back protocol, correlating chimaerism results with transplant outcomes. T lymphocyte (CD3 + cells) and myeloid (CD14 + /CD15 + cells) lineage specific chimaerism was measured regularly in the first 3 months post-transplant. Here we describe factors associated with mixed chimaerism, and the relationship between early mixed chimaerism and transplant outcome in patients with haematological malignancies receiving TCD human leucocyte antigen (HLA)-identical PBSCT and delayed DLI. SummarySixty patients with haematological malignancies received a myeloablative regimen of total body irradiation, cyclophosphamide and fludarabine followed by a T-cell-depleted peripheral blood stem cell transplant from a human leucocyte antigen identical sibling. To improve donor immune function, 1 · 10 7 CD3 + cells/kg were added-back between d 45 and 100. Tcell and myeloid chimaerism were monitored regularly to evaluate the effect of T-cell chimaerism on outcome. The major factor affecting outcome was disease risk, with significantly lower relapse and higher survival in 29 standard risk (SR) patients compared with 31 patients at high risk (HR) for treatment failure (relapse 4AE8 ± 5% vs. 59 ± 11%, P < 0AE0001, and overall survival 93 ± 5% vs. 39 ± 10%, P < 0AE0001, respectively). Donor myeloid chimaerism reached ‡95% within 14 d of transplant, but in the first several months, donor T-cell chimaerism was frequently mixed. Full T-cell chimaerism was significantly more frequent in HR vs. SR patients. Landmark analysis at days 30 and 90 in HR patients with mixed versus full T-cell chimaerism, sho...

Chimerism does not predict for outcome after alemtuzumab-based conditioning: lineage-specific analysis of chimerism of specific diseases may be more informative

“…In contrast, patients in our cohort with mixed donor chimerism (MDC, n ¼ 59) at day þ 100 had a more favourable outcome (2-year OS, disease-free survival (DFS) and TRM of 69.7 vs 43.5% (P ¼ 0.03), 65.4 vs 43.7% (P ¼ 0.03) and 8.7 vs 37.2% (Po0.01)) and did not have an increased relapsed incidence when compared to patients attaining early FDC (MDC: 27.1% vs FDC: 25.1%, P ¼ 0.73). This is consistent with data published by Montero et al 9 using T-cell depletion in a myeloablative conditioning regimen, where patients with persistent mixed donor chimerism (MDC) had no increased risk of disease relapse. In both studies, patients with MDC were considered for pre-emptive donor lymphocyte infusions (DLI).…”

“…[5][6][7][8] In contrast, while some early studies have linked the presence of early mixed donor chimerism to subsequent relapse, these data have been both confirmed and contradicted in other studies. 9,10 We recently evaluated the results of 110 patients receiving alemtuzumab-based reduced intensity conditioning for MDS and AML, using a regimen of 30 mg/m 2 i.v. fludarabine daily from day À9 to day À5; 4 mg/kg oral BU in four divided doses daily from day À3 to day À2; and 20 mg i.v.…”

Donor CD4 T cells convert mixed to full donor T-cell chimerism and replenish the CD52-positive T-cell pool after alemtuzumab-based T-cell-depleted allo-transplantation

“…25,26 Nevertheless, most TCD patients with mixed TCC have been treated preemptively with DLI to prevent graft rejection and disease relapse, although with a significant risk of severe GVHD. 27 Our study shows that mixed TCC occurring after TCD allo-transplantation can be reliably converted to full donor TCC by CD8 depl DLI.…”

Early recipient chimerism testing in the T- and NK-cell lineages for risk assessment of graft rejection in pediatric patients undergoing allogeneic stem cell transplantation

“…Several reports have documented the relevance of T-and NK-cell chimerism in the prediction of graft rejection in different transplant settings, particularly in the context of RIC. 5,6,8,9,23,24,26,[32][33][34][35][36][37][38][39][40] To date, only few trials have addressed the correlation of chimerism patterns and graft rejection in the MA setting. 5,20,27,41,42 This study was performed to address the potential significance of lineage-specific chimerism for prediction of graft rejection at the earliest possible time point after transplantation, in order to provide a basis for timely therapeutic intervention.…”