Despite the lower toxicity profile associated with NST, toxicities associated with conventional myeloablative transplantation along with unique complications can occur. As with a conventional myeloablative transplantation, recipients may still experience myelosuppression, GVHD, and other regimen related toxicities, however the overall severity is less.11
The degree and length of anemia, thrombocytopenia, and neutropenia have been reported as less in NST recipients than conventional myeloablative transplant recipients.11
This translates into fewer red cell and platelet transfusions, decreased overall risk of infection, and shorter duration of intravenous antibiotics. In addition, NST conditioning regimens are overall less emetogenic in addition to being associated with fewer cases of regimen related mucositis.11
Absence of mucositis allows the recipient to maintain a reasonable nutritional status, reducing the need for total parenteral nutrition as compared to the conventional myeloablative transplant recipient.
The presentation of GVHD is not unique in the setting of NST however the time of onset can be quite variable. Acute GVHD after NST commonly occurs 6 – 12 months after transplant compared to a more immediate onset, as early as one month, following conventional myeloablative transplantation.30
This delay and variability in onset is related to the gradual engraftment of donor lymphocytes and any subsequent donor lymphocyte infusions. Similar to acute GVHD, the onset of chronic GVHD in NST may be slightly delayed with more extensive disease.31
Although the onset of GVHD in NST varies compared to conventional myeloablative transplantation, the overall incidence appears to be similar or slightly lower.14,30
The lower incidence of acute GVHD may be due to the less intense conditioning regimen resulting in lower toxicity and tissue damage, thus minimizing the release of inflammatory cytokines that may contribute to the development to acute GVHD.30
In NST recipients, the incidence of grade II-IV acute GVHD ranges from 41 to 50%, with a lower incidence of grade III & IV than conventional myeloablative transplantation.13
The incidence of chronic GVHD is approximately 39% with about 20% classified as extensive.13
Despite the older age and comorbidities of NST recipients, treatment related mortality attributed to GVHD is reported as similar or lower to that of conventional myeloablative transplantation. Incidence of GVHD mortality in NST ranges between 27% - 37%, with the highest rates in patients over the age of 50.2,5
Although many toxicities have been documented to be less prevalent in NST recipients,32
an increased risk of graft rejection, and unique complications such as ABO incompatibility, have been documented and are primarily related to the mixed chimeric state during engraftment. The NST regimen preserves some host T-cells and creates an increased risk of rejection compared to conventional myeloablative transplantation. Therefore, the NST conditioning regimen includes strategies that target host residual immunity to limit graft rejection. Despite this risk, successful rates of engraftment average 94% across various NST regimens with a slightly higher rate in RIC compared to NMC.2
A unique complication, as a result of a mixed chimeric state, is ABO incompatibility. Hemolysis and pure red cell aplasia have been identified with major and minor ABO incompatibilities in NST.33,34
The first, a delayed hemolysis, is a “major” ABO incompatibility, which presents when persistent recipient B-lymphocytes produce antibodies (anti-donor isohemagglutinins) against emerging donor red cells. For example, in a donor with type ‘A’ blood and a recipient with type ‘O’ blood, the recipient produces anti-A isohemagglutinins that react against the donor type A red blood cells. The result is a gradual hemolysis as delayed donor erythropoiesis increases, resulting in red cell aplasia approximately 20-30 days after transplant. Patients with a major ABO incompatibility should be monitored for falling hematocrit and receive red blood cell transfusions if hemolysis is suspected.
The second category of ABO incompatibility is more acute and occasionally fatal.33
This “minor” ABO incompatibility presents as early as 7-14 days after transplant. In this case the donor B-lymphocytes contained in the peripheral blood stem cell product produce antibodies (anti-host isohemagglutinins) against the residual recipient red blood cells. For example, in a donor with type ‘O’ blood and a recipient with type ‘A’ blood, the transplanted donor anti-A isohemagglutinins react against the recipient type ‘A’ red blood cells. The result is an acute hemolysis requiring aggressive management. Management of hemolysis requires frequent monitoring to evaluate the presence of hemolysis and if necessary, red blood cell transfusions. Peripheral blood stem cells contain significantly more B-lymphocytes than bone marrow and therefore may trigger a higher production of donor anti-host isohemagglutinins and thus a more intense hemolysis.34
Bi-directional ABO incompatibility may also occur; where both minor and major incompatibilities are present (e.g. donor type ‘A’ and recipient type ‘B’).
Complications following NST might also include those resulting from older age, pre-existing debility, or advanced disease. In transplant recipients it has been documented that older age and high levels of symptom distress at the time of HSCT were associated with higher levels of distressing symptoms at time of hospital discharge.35
Although NST patients experience less regimen related toxicity than conventional myeloablative transplant patients,13
individuals selected for RIC regimens report high levels of symptom distress prior to HSCT.36
In addition, solid tumor recipients may present for HSCT after surgical resections while older more debilitated recipients may have mild organ dysfunction, diabetes, vascular disease, hyperlipidemia, or other factors that impact their response and tolerance to medications and routine complications. Moreover, patients with chronic diseases may present in a de-conditioned state with mild organ dysfunction due to a history of multiple treatments prior to allogeneic HSCT. A thorough knowledge of an individual's baseline status is essential to identifying and managing subsequent transplant related complications.