Predominant or complete recipient T‐cell chimerism following alemtuzumab‐based allogeneic transplantation is reversed by donor lymphocytes and not associated with graft failure

Abstract

Summary The clinical significance of mixed chimerism following allogeneic haematopoietic stem cell transplantation (HSCT) remains controversial. Its relevance and incidence are probably influenced by the conditioning regimen and incorporation of T‐cell depletion. The presence of recipient chimerism levels >40–50% following T‐cell replete reduced intensity transplantation correlates with a high risk of graft rejection, regardless of donor‐lymphocyte infusions, but it is unclear whether this finding translates to T‐cell depleted transplants. We conducted a retrospective single‐institution analysis of patients receiving alemtuzumab‐based HSCT. 27/152 (18%) evaluable cases had predominantly recipient T‐cell chimerism at 3 months or beyond. By contrast, coincident chimerism in the granulocyte lineage was predominantly of donor origin (median 100%) in all but one patient. Donor lymphocyte infusion effectively converted predominantly recipient T‐cell chimerism to ful donor chimerism in all evaluable cases including three cases with no detectable donor T cells. The only graft failure occurred in the patient with predominantly recipient myeloid chimerism in whom rejection occurred rapidly before donor lymphocytes could be administered. We conclude that predominant or complete recipient T‐cell chimerism following alemtuzumab‐based regimens does not have the same clinical implications as that following T‐cell replete transplants and can be effectively converted with donor lymphocytes without the need for lympho‐depleting agents or re‐conditioning.

Preemptive DLI without withdrawal of immunosuppression to promote complete donor T-cell chimerism results in favorable outcomes for high-risk older recipients of alemtuzumab-containing reduced-intensity unrelated donor allogeneic transplant: a prospective phase II trial

“…Alemtuzumab-based conditioning has been associated with high rates of persistent mixed donor T-cell chimerism, which has been associated in some studies with increased relapsed rates. [12][13][14] Administration of DLI has been shown to promote full-donor chimerism 15 and this may result in lower relapse rates. 14,[29][30][31][32] We postulated that early mixed T-cell chimerism may be effectively converted to full-donor T-cell chimerism by using preemptive low-dose DLI, even in the absence of relapse or persistence of malignancy.…”

“…Engraftment and chimerism Sustained donor engraftment occurred in 35 (97%) of 36 patients, with a median (range) time to neutrophil and platelet recovery of 16 (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and 16 (0-42) days, respectively. One patient had primary graft failure.…”

“…[12][13][14] In patients with persistent MC, DLI has been utilized to convert patients to fulldonor chimerism. 15 However, DLI is typically administered following the withdrawal of immunosuppressive therapy and can result in GVHD. In this study, we tested the following hypotheses: (a) that the use of low-dose alemtuzumab (43 mg total dose) would effectively prevent GVHD while resulting in a lower rate of infection and relapse following reduced-intensity conditioning UD transplantation and (b) that in patients with persistent MC following transplantation, the early use of low-dose DLI without withdrawal of immunosuppression would result in complete donor T-cell chimerism without excessive GVHD and further assist in preventing relapse of malignancy.…”

CMV promotes recipient T-cell immunity following reduced-intensity T-cell–depleted HSCT, significantly modulating chimerism status

“…A semiquantitative method based on short tandem repeat region analyses was used as previously described. 7,9,10 Percentage donor chimerism was calculated from informative short tandem repeat regions based on peak height measured in relative fluorescent units (RFUs) by the following formula: % donor chimerism 5 RFU donor-specific fragment/ (RFU donor-specific fragment 1 RFU recipient-specific fragment) 3 100.…”

Emerging drugs for prevention of graft failure after allogeneic hematopoietic stem cell transplantation

“…Because unmanipulated BM or PBSC boost can induce GVHD, CD34 selection or other forms of T-cell depletion of the graft have been assessed in that setting [60]. By contrast, in patients with low or decreasing donor T-cell chimerism levels but still good marrow function, donor lymphocyte infusions have been used in an attempt at preventing impending graft rejection [61,62]. While this approach was successful in patients given T-cell-depleted grafts or in vivo T-cell depletion [62], donor lymphocyte infusions failed to prevent graft rejection in the majority of patients given unmanipulated grafts [61], as observed in the preclinical canine model of transplantation [63].…”