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Targeted busulfan/cyclophosphamide (TBU/CY) for allogeneic hematopoietic cell transplantation (HCT) carries a high risk of sinusoidal obstruction syndrome (SOS) in patients transplanted for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from TBU/CY to CY/TBU) will reduce SOS and day +100 non-relapse mortality (NRM). We enrolled 51 patients with myelofibrosis (n=20), acute myeloid leukemia (AML, n=20), or myelodysplastic syndrome (MDS, n=11) in a prospective trial of CY/TBU conditioning for HCT. Cyclophosphamide 60 mg/kg/day IV for two days was followed by daily IV BU for four days, targeted to a concentration at steady state (Css) of 800–900 ng/mL. CY/TBU-conditioned patients had higher exposure to CY (p<0.0001) and lower exposure to 4-hydroxyCY (p<0.0001) compared to TBU/CY-conditioned patients. Clinical outcomes were compared with controls (n=271) conditioned with TBU/CY for the same indications. In patients with myelofibrosis, CY/TBU conditioning was associated with a significantly reduced incidence of SOS (0% vs. 30% after TBU/CY, p=0.006), while SOS incidence was low in both cohorts with AML/MDS. Day +100 mortality was significantly lower in the CY/TBU cohort (2% vs. 13%, p=0.01). CY/TBU conditioning markedly impacted CY pharmacokinetics and was associated with significantly lower incidences of SOS and day +100 mortality, suggesting that CY/TBU is superior to TBU/CY as conditioning for patients with myelofibrosis.

Long term complications following hematopoietic cell transplantation (HCT) have undergone comprehensive study. Although virtually every organ system can be adversely affected after HCT, the underlying pathophysiology of these late effects are incompletely understood. This manuscript describes current understanding of the pathophysiology of late effects involving the gastrointestinal, renal, cardiac, pulmonary systems along with a discussion of post-HCT metabolic syndrome studies. The patient’s underlying disease, pretransplant exposures, transplant conditioning regimens, graft versus host disease (GVHD) and other therapies contribute to these problems. Because organ systems are interdependent, long term complications with similar pathophysiology often involve multiple organ systems. Current data suggest that post-HCT organ complications occur as a result of cellular damage that leads to a cascade of complex events. The interplay between inflammatory processes and dysregulated cellular repair likely contributes to end-organ fibrosis and dysfunction. Though many long term problems cannot be prevented, appropriate monitoring can lead to detection and organ-preserving medical management at earlier stages. Currently, management strategies are aimed at minimizing symptoms and optimizing function. There remain significant gaps in knowledge regarding pathophysiology of therapy-related organ toxicities disease following HCT. These gaps can be filled by closely examining disease biology and defining which patients are at highest risk of adverse outcomes. In addition, strategies should be developed for targeted disease prevention and health promotion efforts for individuals at high risk because of their genetic makeup or specific exposure profile.

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