From risk indices to reconstitution of immunity : studies of outcome-related factors in patients undergoing allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potent immunotherapeutic procedure which has the possibility to cure otherwise lethal hematological diseases. Its usability in clinical practice is limited by tangible risks of detrimental transplantation-related complications. Consequently, it is of great importance to adjust eligibility criteria and individualize allogeneic HSCT treatment protocols to maximize the chance of a positive outcome for every single patient. The general aim of this thesis has been to study influential outcome-related factors in patients under-going allogeneic HSCT. In the enclosed research papers, specific focus has been directed to improve interpretations of patient comorbidity and hematological indication prior to transplantation (paper I), to optimize stem cell dose (paper II), the choice of graft-versus-host disease (GVHD) prophylaxis (paper III) and to evaluate immune reconstitution after treatment (paper IV).

In scientific paper I, we performed a retrospective study of 521 consecutive adult allogeneic HSCT-patients transplanted at the Karolinska University Hospital for hematological malignancy from 2000 to 2012 to compare the predictive capacity of the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) and the disease risk index (DRI) for transplantation-related mortality (TRM) and overall survival (OS). Both indices could predict OS (with poorer survival in the highest risk groups) but failed to predict differences in TRM. In summary, obtained study data showed that the studied indices should be evaluated according to local data prior to their implementation on individual patients on the single-center level. For patients with pre-existing comorbidities, the use of reduced intensity conditioning regimens (RIC) has made allogeneic HSCT a valid treatment option.

In scientific paper II, we sought to determine the optimal hematopoietic stem cell dose (CD34+ cell dose) related to survival in RIC transplantations with peripheral blood stem cell grafts (PBSCT). Using consecutive transplantation registry data from the Center for International Blood and Marrow Transplant Research (CIBMTR), we retrospectively analyzed 1,054 patients with AML or MDS who underwent RIC PBSCT between 2002 and 2011. Grafts from HLA-matched siblings containing < 4 × 106 CD34+ cells/kg recipient and grafts from unrelated donors containing < 6 ×106 CD34+ cells/kg recipient, were associated with higher overall mortality after transplantation. Consequently, CD34+ cell dose in PBSCT grafts should be kept above these respective thresholds if possible.

In scientific paper III, we compared the standard GVHD prophylaxis regimen of cyclosporine and methotrexate (CsA/Mtx, n = 106) with a combination of tacrolimus and sirolimus (Tac/Sir, n = 103) in a prospective randomized trial. Based on previous publications on sirolimus, the hypothesis was that Tac/Sir would lead to less acute GVHD and reduced TRM. Analyses of study data did not show any significant differences in incidence of grades II-IV acute GVHD between the groups (CsA/Mtx: 41%, Tac/Sir: 51%), and data for TRM and OS were similar. In conclusion, the two GVHD prophylaxes provided comparable outcomes in patients after matched related or unrelated allogeneic HSCT, but study data indicated differences in toxicity in certain transplantation settings. GVHD prophylaxis and conditioning regimens constitute risk factors for prolonged immuno-deficiency related to impaired transplantation outcomes.

In scientific paper IV, we sought to investigate the effects of the two different GVHD prophylaxis protocols (from paper III) on lymphocyte reconstitution and replicative capacity using PCR-derived levels of TREC, KREC and telomere length as proxy markers. Levels of lymphocyte excision circles were not significantly different between the GVHD prophylaxis groups, but patients with TREC or KREC levels above median during study follow-up had reduced TRM and superior OS.

In summary, the results and conclusions presented in this thesis may be useful in the continuous endeavor towards a safer and more individualized allogeneic HSCT procedure for future patients. Either as arguments for adjusted transplantation protocols or as basis for future research hypotheses.

List of scientific papers

I. Impact of pretransplantation indices in hematopoietic stem cell transplantation: knowledge of center-specific outcome data is pivotal before making index-based decisions. Törlén J, Remberger M, Le Blanc K, Ljungman P, Mattsson J. Biol Blood Marrow Transplant. 2017 Apr; 23(4):677-683.
https://doi.org/10.1016/j.bbmt.2017.01.003

II. Low CD34+ dose is associated with poor survival after reduced intensity conditioning allogeneic transplantation for acute myeloid leukemia and myelodysplastic syndrome. Törlén J, Ringdén O, Rademacher JL, Batiwalla M, Chen J, Erkers T, Ho V, Kebriaei P, Keever-Taylor C, Kindwall-Keller T, Lazarus HM, Laughlin MJ, Lill M, O’Brien T, Perales MA, Rocha V, Savani BN, Szwajcer D, Valcarcel D, Eapen M. Biol Blood Marrow Transplant. 2014 Sep; 20(9):1418-1425.
https://doi.org/10.1016/j.bbmt.2014.05.021

III. A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation. Törlén J, Ringdén O, Garming-Legert K, Ljungman P, Winiarski J, Remes K, Itälä-Remes M, Remberger M, Mattsson J. Haematologica. 2016 Nov; 101(11):1417-1425.
https://doi.org/10.3324/haematol.2016.149294

IV. Effect of graft-versus-host disease prophylaxis regimens on T and B cell reconstitution after allogeneic hematopoietic stem cell transplantation. Törlén J, Gaballa A, Remberger M, Mörk LM, Sundberg B, Mattsson J, Uhlin M. Biol Blood Marrow Transplant. 2019 Jan. [Accepted]
https://doi.org/10.1016/j.bbmt.2019.01.029