ABO Incompatible Allogeneic Stem-Cell Transplantation Following Reduced-Intensity Conditioning: Close Association with Thrombotic Microangiopathy.

Thrombotic microangiopathy (TM) is a severe complication of stem cell transplantation (SCT) associated with high mortality rates. One of the major risk factors for the development of TM is the toxic effect of high-dose chemo-radiotherapy, heavy pretreatment and the use of unrelated donors (URD) grafts. To reduce transplant related mortality in patients at risk non myeloablative conditioning regimens have been introduced.

We reviewed data on 83 consecutive patients given sibling (n=44) and URD (n=39) SCT after reduced intensity conditioning and graft versus host (GvHD) prophylaxis with CsA and mycophenolate mofetil with respect to occurence of TM. Diagnoses consisted of ALL (n=5), AML (n=31), CML (n=8), MDS (n=6), MM (n=11), NHL (n=17), renal cell cancer (n=4) and n. ovarii (n=1). A group of 565 patients undergoing high-dose conditioning followed by sibling (n=372) an URD (n=193) SCT served as control. The majority of these patients received CsA and MTX as GvHD prophylaxis. The diagnoses of TM was confirmed by renewed thrombocytopenia, coombs negative hemolysis, increased LDH-levels and fragmented red cells in peripheral blood smears. TM occured in 9 of 83 patients (11%) after RIC compared to 25 of 565 patients (4,4%) after high-dose conditioning, respectively. All but one patient in the RIC group received an ABO-incompatible stem cell graft (p< 0.05). The median time of onset of TM was 62 days after SCT (range, 9 to 906 days) in this group. Donor source (sibling/URD) had no influence on the risk of developing TM (p=0.07). TM was associated with severe acute GvHD (n=2), chronic extensive GvHD (n=3), sepsis (proteus mirabilis n=1), herpes virus infection (n=1), severe hemolysis after minor ABO-incompatible SCT (n=1) and computed tomography approven atypical pneumonia (n=1). First line treatment consisted of withdrawal of cyclosporine A and plasmaexchange treatment (median exchange procedures 14, range 8 to 30). Overall, 5of 9 (55%) patients responded, 3 patients died due to GvHD and TM, 1 of multi- organ failure. One patient who responded to plasmaexchange died 1 year later due to relapse.

Posttransplant TM is a common severe complication and seems to increase after reduced-intensity conditioning. Fludarabin, a major constitute of RIC, is not reported to cause TM. How far GvHD-prophylaxis without MTX plays a role in the development of TM remains unclear. Of particular importance is that patients receiving ABO-incompatible stem cell grafts have a significant higher risk to develop TM after allogeneic SCT following reduced-intensity conditioning.