Risk-factors, prevention and treatment of early complications after allogeneic haematopoietic stem cell transplantation

Abstract

The aims of this thesis were to define risk factors for early complications after allogeneic haematopoietic stem cell transplantation (HSCT), such as bacteraemia during the aplastic phase, veno-occlusive disease in the liver (VOD) and acute graft-versus-host disease (GVHD). Furthermore, we wanted to evaluate new methods - e.g., intraosseous infusion, peripheral blood progenitor cell transplantation (PBPCT) and granulocyte-colony stimulating factor (G CSF) post-transplant treatment for a shorter neutropenic period. And finally, we aimed to evaluate the effects and side-effects of recombinant tissue plasminogen activator (rt-PA) treatment and liver transplantation for VOD.

In 500 consecutive patients who underwent allogeneic HSCT in Huddinge Hospital between November 1975 and June 1995, receiving HSC from an unrelated donor was found to be the only significant risk factor (p<0.01). In 251 patients grafted between January 1990 and June 1995, the following risk factors were associated with an increased risk of hepatic veno occlusive disease in multivariate logistic regression analysis: norethisterone treatment after transplantation (p<0.001), bilirubin level >26 µmo/l before transplantation (0.002), HLA mismatched donor (p=0.003), previous abdominal irradiation (0.02) and busulphan treatment (0.02). Heparin prophylaxis (100 IE/kg/24 hours), given from the start of the conditioning regimen until one month after BMT or discharge, did not influence the incidence or mortality rate of VOD.

In 291 patients grafted with marrow from HLA-identical sibling donors between November 1975 and June 1993, the main risk factors for acute GVHD in logistic regression, multivariate analysis were: immunosuppression with monotherapy (CsA or MTX) (p=0.01), pretransplant multiple-positive donor herpes virus serology (p=0.01), early engraftment (p=0.02) and CMV seropositivity in the recipient before BMT (p=0.04).

Thirty-eight patients receiving marrow transplants from related donors were randomized to i.o. + i.v. (n=10), i.o. (n=8) or i.v. (n=20) infusions of bone marrow. We found a significant reduction in the number of days on TPN (p=0.03) and a tendency to a reduction in the number of days on antibiotics, using the i.o. technique (p=0.06). However, intraosseous, compared to intravenous administration of bone marrow, did not accelerate haematological recovery.

Twenty-three recipients of peripheral blood progenitor cells (PBPC) were matched with 23 recipients of bone marrow (BM). Eleven in each group were recipients of unrelated HSC. A higher number of MNC (p<0.001), CD34+ (p=0.05), CD3+ (p<0.001) and CD56+ (p<0.001) cells in the graft, a reduced number of platelet transfusions (p=0.03) and a significant hastening of neutrophil (ANC >05x109/l, 12 vs. 17 days after HSCT, p<0.001) and platelet recoveries (>30x109/l, 15 vs 20 days, p=0.02) were seen in the PBPC group, compared to the BM group. Sixty-nine patients were randomized to G-CSF (5 µglkg/day) treatment, starting on day 0 (n=23), day +5 (n=23) and day +10 (n=23), respectively, after unrelated HSCT. G-CSF treatment starting on day +10 was found to be as effective in improving neutrophil recovery as starting on day +5 or on the day of transplantation (day 0). Starting treatment on day +10, rather than on day 0, reduced the costs of G-CSF by $1060. The 69 patients given G-CSF reached ANC>O.sx109/l a median of 5 days earlier than a retrospective control group of 30 recipients of unrelated HSC not given G-CSF (p=0.004), and they were discharged a median of 8 days earlier from hospital (p=0.04). Treatment with rt-PA (n=8), rt-PA+OLT (n=2) and OLT (n=1) for severe VOD was evaluated in 11 recipients of allogeneic bone marrow.

Our findings suggest that rt-PA should not be given in high doses and not over a long period, because of the risk of severe haemorrhages. In patients with irreversible VOD, OLT may be considered in selected patients.