Incidence, Risk Factors, and Prognosis of Late Immune-Mediated Disorders after Allogeneic Hematopoietic Cell Transplantation (HCT)

Background: Chronic graft-versus-host disease (cGVHD) remains a major barrier to successful use of HCT. The incidence, clinical presentation, course, and outcomes of GVHD-related syndromes are not well described in a multi-center setting.

Methods: The Chronic GVHD Consortium enrolled allogeneic HCT recipients in a prospective, longitudinal, observational study, and followed them closely for development of four GVHD-related syndromes: Late acute GVHD, cGVHD (both defined according to NIH consensus criteria), bronchiolitis obliterans syndrome (BOS), and cutaneous sclerosis (CS). Participants were enrolled up to 121 days after HCT as long as they had not already developed a late immune-mediated disorder. Research samples were drawn at day 100 and again at day 180 or 365 post HCT.  Subjects who developed GVHD syndromes underwent additional sampling and data-collection.

Results: Allogeneic HCT recipients (N=913) were enrolled at 13 centers from March 2011 to May 2014. The cumulative incidence of cGVHD was 51% with a median onset of 7.3 months (Table), and 86% of cGVHD cases were diagnosed within the first year after HCT. Late acute GVHD and BOS had particularly poor survival with 29% and 36% non-relapse mortality (NRM) at 2 years after syndrome onset. In multivariable analysis, KPS < 80% at HCT (HR: 2.6, 95% CI:1.6-4.0, p<0.001) was associated with a higher risk of late acute GVHD. Unrelated cord blood transplantation (UCBT) was associated with a lower risk of cGVHD (HR 0.5, 95% CI 0.3-0.7, p<0.001). At 2 years after HCT the probability of GVHD-free, relapse-free survival was 21% (95% CI: 17%-24%) including only the late immue-mediated disorders, and 9% (95% CI: 7%-12%) if classic acute GVHD was included as an event.

Conclusions: This is the first prospective study evaluating incidence and outcomes of GVHD-related syndromes. The onset of the syndromes varied from a median of 5.2 to 13.5 months after HCT, indicating need for continuous close monitoring and management.  Amongst the GVHD-related syndromes, late acute GVHD and BOS have particularly poor overall survival, indicating a need for more effective treatments. Since research samples were banked, further studies examining biologic correlates of these syndromes are planned. Investigators interested in access to data or samples should contact the Chronic GVHD Consortium. (http://www.rarediseasesnetwork.org/cgvhd/about/ OR chronicgvhdstudies@fhcrc.org).

Table:

Syndrome	Number of cases	Cumulative incidence at 2 years (95% CI)	Median time to onset, mos (range)	NRM 2 years after onset (95% CI)	Survival 2 years after onset (95% CI)
Late acute GVHD	85	11% (9%-14%)	5.2 (3.2-15.6)	29% (15%-54%)	57% (33%-76%)
Chronic GVHD	339	51% (47%-55%)	7.3 (1.8-22.0)	17% (11%-26%)	77% (67%-84%)
BOS	25	5% (3%-8%)	11.4 (2.8-21.7)	36% (15%-90%)	62% (22%-86%)
CS	44	10% (7%-13%)	13.5 (4.0-26.5)	12% (4%-36%)	88% (65%-96%)