Outcome after allogeneic stem cell transplantation with special reference to non-malignant disorders, chimerism and graft cell composition

The outcome for patients undergoing allogeneic stem cell transplantation (HSCT), a treatment for several severe malignant and non-malignant disorders with hematopoietic origin, is a balancing act between beneficiary effects and risk factors. Treatment success is still limited by excessive immune response, such as graft-versus-host–disease (GVHD) and graft failure (GF), or the lack thereof as in malignancy relapse or severe infections. The main focus of this thesis is to evaluate treatment outcome of different patient groups and evaluate the effect of routine testing for these patients.

In 2004, the decision to use an unrelated donor (URD) rather than a HLA-identical sibling for patients with a non-malignant disorder was, due to a higher risk for complications, more debatable than today. In Paper 1, we retrospectively analysed the outcome for 25 patients with non-malignant disorders who underwent HSCT with a unrelated HLA-A,B DRβ1-matched donor. All patients received anti-thymocyte globulin (ATG). Only 2 patients rejected their graft and the cumulative incidence of acute (only grade I and II were diagnosed) and chronic GVHD was 24%, and 21%, respectively. Also, the overall survival (OS) was 84% indicating that the results were comparable to patients undergoing a HSCT with a HLA-identical donor.

Chimerism is a PCR-based technique used to determine the genotypic cell origin of post transplantation hematopoiesis for the detection of graft failure (GF) and relapse. Post HSCT, we can find either a mix of donor and recipient, i.e. mixed chimerism (MC) or only cells of donor origin i.e. donor chimerism (DC). In Paper 2, we retrospectively evaluated 58 patients (64 transplants) with non-malignant disorders and studied the outcome in relation to chimerism status and, in addition, how high MC was clinically managed (to avoid GF). We found MC in 64% of the transplants. Donor chimeric (DC) was more common after myeloablative conditioning (MAC) than after reduced conditioning (p=0.04), and patients with DC had a higher incidence of acute GVHD grade II–III (p=0.002) compared to patients with MC. Owing to high MC, no conclusive treatment was established, but patients with GF who underwent a re-HSCT did well.

Outcome for adult patients after HSCT have improved. In Paper 3, we compared outcome after HSCT for pediatric patients between time periods 1992-2002 (P1) and 2003 to 2013 (P2). The most significant changes during P2 compared with P1 were a decrease in MAC protocols, altered GVHD prophylaxis and more eligible patients had a non-malignant diagnoses (p=0.002). Results showed more acute GVHD, less transplanted mortality (TRM) but relapse rate was unchanged. In all, 3-year overall survival (OS) improved from 58% in P1 to 78% in P2 (p<0.001).

Lastly, pursuing the quest for relevant factors influencing patient outcome, its known that donor grafts entail not only stem cells (CD34+) but also potentially active lymphocytes whose numbers can differ depending on the donor and donor site. In Paper 4, we hypothesized that these donor graft lymphocyte sub-sets could influence patient outcome. We collected and evaluated routine flow cytometry donor graft data (i.e. CD34+, CD3+, CD19+, CD4+, CD8+, CD3-CD56+CD16+, CD4+CD127lowCD25high) for 299 patients with malignant diseases who underwent HSCT between 2006 and 2013 with peripheral blood stem cell grafts (we analysed unrelated separated from sibling donors). The multivariate analysis showed in the unrelated-group an association between a high CD8+ graft dose and decreased risk for relapse (p=0.006) and in the sibling group a high CD19+ graft dose was associated with increased risk for transplanted related mortality (p=0.036) and acute GVHD (p=0.003).

List of scientific papers

I. Allogenic stem cell transplantation for nonmalignant disorders using matched unrelated donors. Svenberg P, Remberger M, Svennilson J, Mattsson J, Leblanc K, Gustafsson B, Aschan J, Barkholt L, Winiarski J, Ljungman P, Ringdén O. Biology of Blood Marrow Transplantation. 2004 Dec;10(12):877-82.
https://doi.org/10.1016/j.bbmt.2004.08.002

II. Allogeneic hematopoietic SCT in patients with non-malignant diseases, and importance of chimerism. Svenberg P, Mattsson J, Ringdén O, Uzunel M. Bone Marrow Transplantation. 2009 Dec;44(11):757-63.
https://doi.org/10.1038/bmt.2009.82

III. Improved overall survival for pediatric patients undergoing allogeneic hematopoietic stem cell transplantation - A comparison of the last two decades. Svenberg P, Remberger M, Uzunel M, Mattsson J, Gustafsson B, Fjaertoft G, Sundin M, Winiarski J, Ringdén O. Pediatric Transplantion. 2016 Aug;20(5):667-74.
https://doi.org/10.1111/petr.12723

IV. The importance of graft cell composition to outcome after allogeneic stem cell transplantation in patients with malignant disease. Svenberg P, Wang T, Uhlin M, Watz E, Remberger M, Ringden O, Uzunel O. [Submitted]