Invasive fungal disease (IFD) is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HCT). We performed a retrospective review of 271 adults with a hematologic malignancy undergoing allogeneic HCT to determine the incidence of and risk factors for IFD and to examine the impact of IFD on nonrelapse mortality and overall survival. We defined IFD using standard criteria and selected proven and probable cases for analysis. Diagnoses in the study group included acute leukemia (42%), non-Hodgkin lymphoma (24%), myelodysplastic syndrome (15%), chronic lymphocytic leukemia (5%), and other hematologic disorders (14%). Conditioning included reduced-intensity (64%) and myeloablative (36%) regimens. Donor sources were HLA-matched sibling (60%), matched unrelated (20%), haploidentical (12%), and cord blood (8%). A total of 51 episodes of IFD were observed in 42 subjects (15%). Aspergillus spp (47%) was the most frequent causative organism, followed by Candida spp (43%). The majority of IFD cases (67%) were reported after day +100 post-HCT. In multivariate analysis, haploidentical donor transplantation (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.49-9.77; P = .005) and grade II-IV acute graft-versus-host disease (HR, 2.55; 95% CI, 1.07-6.10; P = .03) were risk factors for the development of IFD. Conversely, higher infused CD34(+) cell dose was associated with a lower risk of IFD (HR, 0.80; 95% CI, 0.68-0.94; P = .006, per 1 × 10(6) cells/kg increase in CD34(+) cell infusion). IFD-related mortality was 33.3%. Nonrelapse mortality was significantly higher in patients who developed IFD compared with those without IFD (P < .001, log-rank test). Patients with IFD had lower overall survival (5.8 months versus 76.1 months; P < .001, log-rank test). Further studies exploring strategies to increase the infused cell dose and determine adequate prophylaxis, especially against aspergillus, beyond day +100 are needed.

We performed a retrospective study of the engraftment syndrome (ES) as defined by the Spitzer Criteria in adult patients undergoing allogeneic hematopoietic cell transplantation (HCT) for various hematological malignancies at a single institution, over a decade, and analyzed its relationship to acute GVHD; 217 patients underwent either myeloablative (38.7%) or reduced intensity (61.3%) HCT; 22.1% met the criteria for ES. Acute GVHD prophylaxis (P 5 0.006) and transplants prior to 2006 (P < 0.0001) were significantly associated with a risk of ES in univariable analysis. Early aGVHD within 4 weeks of engraftment was significantly more common in the ES compared to the non ES cohort (21 vs. 8.3% respectively, P 5 0.02). ES did not predict for future GVHD, as at day 1180, the cumulative incidences of grades II-IV aGVHD (31 vs. 23%, P 5 0.19) and of chronic GVHD at 2 years of engraftment (42 vs. 36%, P 5 0.28) were not significantly different between the ES and non ES groups, respectively. No significant differences in NRM, overall survival and progression-free survival were observed between the two groups. Although predictive of early aGVHD, ES occurred independently of GVHD in 79% of the patients. Survival outcomes should be evaluated in a larger randomized study to investigate if there is a correlation with ES.

There is little data regarding the incidence, clinical manifestations, risk factors and outcomes of late acute GVHD (aGVHD). We evaluated patients with late aGVHD after allogeneic HCT between 2007 and 2012 and compared their outcomes to patients with early onset aGVHD. Of the 511 allogeneic HCT recipients, 75 developed late aGVHD (cumulative incidence: 14.7% (95% CI: 11.6-17.8) versus 248 with early onset aGVHD (cumulative incidence: 49% (95% CI: 45-53). Amongst those with late aGVHD, 52% had persistent, 39% recurrent and 9% de-novo late aGVHD. Advanced (grade III-IV) early onset aGVHD was associated with a higher risk of developing late aGVHD (HR 1.9, 95% CI: 1.2 −3.1, p= 0.01). 48% (95% CI: 36-60%) of late aGVHD versus only 31% (95% CI: 26-37%) of early onset aGVHD progressed to chronic GVHD by 2 years. Higher proportion of persistent (53%) as compared to recurrent (39%) and de-novo (46%) late aGVHD progressed to cGVHD at 2 years. The overall survival was 59% (95% CI: 49-72) in late aGVHD and 50% (95% CI: 44-57%) in early onset aGVHD. Persistent late aGVHD had worse OS and NRM (45% and 39%) as compared to recurrent (74% and 18%) and de-novo (83% and 0%) late aGVHD. Compared to HLA-identical sibling HCT, unrelated donor transplants were associated with a higher risk of mortality in patients developing late aGVHD (HR 6.1, 95% CI: 2.3-16.2, p<0.01). In a landmark analysis (evaluating 100 day survivors among early onset aGVHD), no difference was seen in late mortality (after 100 days) between early onset and late aGVHD (HR 0.96, 95% CI: 0.59-1.55, p= 0.85), however the risk of cGVHD was nearly doubled (HR 1.81, 95% CI: 1.16-2.82, p=0.01) in patients with late aGVHD. Conclusions: Late aGVHD is a relatively common complication after allogeneic HCT. Poorer outcomes in those with persistent late aGVHD imply need for more effective therapy in this group to improve transplant outcomes. A higher risk of subsequent chronic GVHD needs further evaluation and close monitoring.

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associated with reduced relapse (HR 0.64 in F->M and 0.59 in M->F, P<0.01 in each), while no impact of sex-mismatch on relapse was observed in the MAC or RIC groups (Fig 1). Finally, in the TLI-ATG group, sex-mismatched transplant was significantly associated with superior OS (HR 0.69 in F->M, P¼0.037; HR 0.61 in M->F, P¼0.014), while F->M transplant was significantly associated with inferior OS in the MAC group (HR 1.59, P¼0.018) and no improvement in OS in the RIC group (HR 1.31, P¼0.36) (Fig 2). In the TLI-ATG group, the benefit of sex-mismatched HCT on OS seems due to the reduced relapse rate. We previously reported HY-Ab response post-HCT was associated with chronic GVHD as a representative of allo-Ab response (Nakasone et al. ASH 2013). We then hypothesized that HY-Ab response 3m post-HCT could predict reduced relapse in F->M HCT with TLI-ATG. Relapse incidence at 2 years post-HCT was higher in the recipients who had no HY-Ab response at 3m post-HCT vs. those who did (49% vs. 26%, P¼0.037, Fig 2). Multivariate analysis corroborated that the detection of HYantibodies 3m post-HCT was significantly associated with reduced relapse in F->M HCT with TLI-ATG [HR 0.29, P¼0.039]. Conclusion: We conclude that the benefits and risks of sexmismatch differ according to conditioning intensity/strategy, and is the first reported evidence that sex-mismatched transplant might preferably be selected in TLI-ATG, while avoided in MAC transplantation.