A prospective molecular study of chimaerism in patients with haematological malignancies receiving unrelated cord blood or bone marrow transplants: detection of mixed chimaerism predicts graft failure with or without early autologous reconstitution in cord blood recipients

Abstract

We prospectively studied the chimaerism status in the bone marrow (BM) and peripheral blood (PB) of 23 patients receiving umbilical cord (UCB, 14 cases) or BM (nine cases) transplants from unrelated donors by PCR amplification of four individual-specific VNTR genetic loci. Haematological engraftment, with persistent full donor pattern. was observed in 10/14 (72%) patients receiving UCB and in 9/9 (100%) patients transplanted with marrow from an unrelated donor (MUD). In contrast, the remaining four patients converted to an autologous pattern. Three out of these four patients had an early autologous haematological reconstitution reaching a neutrophil level >0.5 x 10(9)/l at days 27, 33 and 37 after transplant, respectively. In all three of these patients, chimaerism analysis demonstrated an early appearance of donor cells (i.e. within 35 d after UCB transplant) showing a transient full donor (one case) or mixed chimaerism condition (two cases). Despite the early autologous haemopoietic reconstitution, one of the three patients died of GVHD at day 60, which was explained by the demonstration of low levels of donor lymphoid cells. In the MUD group all nine patients converted to a persistent full donor pattern with haematological reconstitution, accompanied in two of them by transient mixed chimaerism lasting to days 60 and 270 after transplant. Our data show that monitoring of chimaerism may predict graft failure with or without early autologous haemopoietic reconstitution in patients receiving unrelated UCB transplants. Furthermore, chimaerism analysis may identify, in patients with autologous reconstitution, those at risk of severe GVHD in whom immunosuppressive therapy should not be discontinued.

Early identification and management of graft failure after unrelated cord blood transplantation

“…Our observation is in keeping with those made in these patients who received other unmanipulated HSC grafts. [26][27][28] Mixed chimerism was found in two of our leukemia patients and both went on to GF. Monitoring chimerism at short time intervals helped to identify the course of these patients.…”

“…Monitoring chimerism at short time intervals helped to identify the course of these patients. Cimino et al 28 showed that mixed chimerism in UCBT recipients before day 35 predicted GF, with or without autologous reconstitution; and a high probability of leukemia relapse. Patients with nonmalignant disorders 26,29 and those who have not received recent chemotherapy 18 are more likely to develop mixed chimerism after HSCT.…”

Second hematopoietic stem cell transplantation for the treatment of graft failure, graft rejection or relapse after allogeneic transplantation

“…39 Rejection may be heralded by incomplete and decreasing donor chimerism, allowing the re-expression of host T cell function. [40][41][42][43] Graft dysfunction is an ominous circumstance and may herald relapse of neoplasm with restoration of host hematopoiesis. [44][45][46] …”

Pre-transplant prognostic factors for patients with high-risk leukemia undergoing an unrelated cord blood transplantation

“…The details on this finding have been reported and extensively discussed elsewhere. 23 The Minnesota group observed autologous hematopoietic recovery in four of 102 patients of its series, but this phenomenon was restricted to patients affected by nonmalignant diseases and followed a secondary graft failure after a primary engraftment. 11 The spontaneous and primary autologous hematopoietic reconstitution occurring early after CBT in leukemic patients conditioned with a highly intensive regimen has been anecdotically reported.…”

“…Chimerism studies were performed on BM and peripheral blood cells at days 20, 35, 60, 100, 180, 270 and 365 after transplant. 23 Engraftment with full chimerism required myeloid hematopoietic recovery with all cells in the recipient of donor origin, while the simultaneous presence of donor and recipient cells was defined as engraftment with mixed chimerism. The absence of hematopoietic recovery at 90 days after transplant and the autologous hematopoietic reconstitution were considered as engraftment failure.…”