Prospective Longitudinal Study of Late Acute Graft Versus Host Disease after Hematopoietic Cell Transplantation: A Report from Chronic Gvhd Consortium

Background: Late acute (LA) graft vs. host disease (GVHD) is persistent, recurrent or new onset acute GVHD symptoms more than 100 days after hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, and the morbidity and mortality associated with LA GVHD.

Methods: A prospective cohort of patients was enrolled as part of an observational study of immune mediated disorders after HCT within the Chronic GVHD Consortium at 13 centers. Patients with previous diagnosis of LA or chronic GVHD prior to enrollment were excluded.

Results: Out of 913 patients in the study, 85 developed LA GVHD with a cumulative incidence of 11% at 2-year after HCT (2-persistent, 40- recurrent and 43 de-novo). Median age was 53.2 years, 70% received URD transplants, and graft source was peripheral blood in 87%. 44% received myeloablative conditioning, and 7% received ATG/ Alemtuzumab. Median time of onset for LA GVHD was 160 days (IQR 128-204) days after HCT. Median follow-up for survivors after LA GVHD diagnosis was 10.2 (range 0.7-25.9) months. 60% of patients had biopsy proven LA GVHD. Single organ involvement at diagnosis was seen in 59 patients (skin 39%, liver 14% and gut 47%), while 26 patients (31%) had ≥2 organ involvement. 21% of patients with liver GVHD had only transaminitis without elevated bilirubin and hence were not included for acute GVHD grading but were included for the other analyses. Initial treatment included beginning or increasing systemic steroids (69%), continuing calcineurin inhibitors (64%) or beginning topical treatment (52%). Additional treatment was added within the first 28 days for 31% patients. Median lines of treatment for the total duration of follow-up were 1 (range 0-4).

Of the evaluable patients, 63/85 and 56/66 had a clinical response (CR/ PR) at 28 days and at 180 days respectively. 36% developed recurrence of LA GVHD after a documented CR. 26% developed chronic GVHD after LA GVHD at a median of 169 (range 25-383) days after diagnosis of LA GVHD. Median number of hospital days in the first 6 months after the diagnosis of LA GVHD was 15 (range 1-120) days. 25% had discontinued immunosuppressive therapy (IST) at the time of last follow-up with the median duration of IST being 12.8 (range 6.1-24.7) months after HCT. 9% relapsed and 22% died with the main causes of death being GVHD, infection or multi organ failure. Median failure free survival (FFS) as defined by absence of relapse, death, addition of new IST or development of chronic GVHD was 3.6 months (95% CI: 1.7-6.8). (Figure) Median overall survival (OS) was 25.3 months. No patient/ transplant or GVHD related factors emerged as significant predictors for FFS or OS in univariate analysis.

Conclusions: The overall incidence of LA GVHD is low, but it is associated with prolonged immunosuppression, poor failure free and overall survival.

Figure: Failure Free survival in patients with late acute GVHD