Incidence and Clinical Characteristics of Chronic Graft Versus Host Disease (cGVHD) According to the National Institutes of Health (NIH) Criteria in Patients Transplanted for Acute Myeloid Leukemia (AML).
Authors: Vega Arturo , Martus Peter , Terwey Theis , Jakob Christian , Vuong Lam G , Hemmati Philipp , le Coutre Philipp D. , Arnold Renate 
Published: October 2019

Abstract
Abstract 4639
Due to the lack of reproducibility and predictive value of former classifications, a new classification for cGVHD was proposed by the NIH in 2005. The former cut off day 100 required to diagnose cGVHD has been omitted and now the diagnosis relies on clinical characteristics. The NIH classification is now evaluated in different transplant centers.

Purpose
Diagnose and classify cGVHD in a retrospective fashion using the NIH criteria. Evaluate the incidence and clinical characteristics of cGVHD in AML transplanted with a myeloablative conditioning regimen (MAC) or with a reduced intensity conditioning (RIC).

Patients and Methods
Allogeneic stem cell transplantations for treatment of AML were performed at Charite Berlin, Germany between 12/1994 and 12/2008. 219 patients (pts) were included in the study. cGVHD was diagnosed, classified and graded according to the NIH criteria by Filipovich et al, Biol Blood Marrow Transplant. in 2005. Prognostic value of cGVHD was analyzed using the landmark method.

Results
The earliest diagnostic feature of cGVHD was found on day 84 post transplantation. 30 pts who died or had active leukemia before day 80 were excluded from the cGVHD analysis, 189 pts could be evaluated. Pts for whom the cGVHD status was unclear after first examination (20% of the sample) were reanalyzed by an independents second examiner. In the RIC group, 55 (62%) pts were transplanted in CR1 and 34 (38%) >CR1. In the MAC group, 56 (56%) pts were transplanted in CR1 and 44 (44%) >CR1. HLA compatibility between donor and recipient was as follows: 35 (39%) pts received a match related transplant (MRD), 36 (41%) pts had a match unrelated transplant (MUD) and 18 (20%) pts had a mismatch unrelated transplant in the RIC group. In the MAC group, 49 (49%) pts received MRD, 1 (1%) patient had a mismatch related transplant, 42 (42%) pts had MUD and 8 pts had a mismatch unrelated transplantation. Bone marrow stem cells were infused in 5 (6%) pts in the RIC group and in 20 (20%)pts in the MAC group. The other pts received peripheral stem cells. The median follow up was 19 months (range 3-96) in the RIC group and 47 months (range 3-146) in the MAC group. In the RIC group 29 (32%) pts developed cGVHD, including 9 pts who progress from late acute GVHD (aGVHD) and in the MAC group, 52 (52%) pts, including 3 pts who progressed from late aGVHD. Median time to develop cGVHD was 165 days (range 95-2385) in the RIC group and 236 days (range 84-1793) in the MAC group. In those pts who developed cGVHD, 39 had a history of aGVHD in the MAC group and 18 in the RIC group. Eleven (38%) pts developed classic and 18 (62%) pts overlap cGVHD in the RIC group, and 19 (37%) pts classic and 33 (63%) pts overlap in the MAC group. Mild, moderate and severe cGVHD was present in 12 (42%), 14 (48%), 3 (10%), and in 14 (27%), 27 (52%), 11 (21%) pts of the RIC and MAC group respectively. In Kaplan Meier Analysis the overall risk for cGVHD was higher in the MAC group in comparison to RIC (p=0.038). The first diagnostic feature of cGVHD was found in the mouth in 23 (79%) pts, skin in 4 (14%) pts and the lung in 2 (7%) of the RIC group and the mouth in 43 (83%) pts, skin in 7 (14%) pts, lung in 1 (1%) pts and muscle in 1(1%) patient in the MAC group. cGVHD was diagnosed on clinical criteria without biopsy in 28 (97%) pts in the RIC group and in 50 (96%) in the MAC group. 19 patients in both groups, who were considered affected by cGVHD in the past according to Shulman classification did not fulfill NIH criteria: 11 pts had late acute GVHD and 8 pts had non diagnostic features. The cumulative incidence of cGVHD at 1 and 2 years was 34% and 46% in the RIC group and 54% and 65% in the MAC group (p=0.038). In the entire sample, overall survival after two years was 61.1% (95%CI 53.5% - 68.7%). No prognostic benefit of cGVHD could be shown for overall survival and only moderate benefit of late cGVHD for disease free survival.

Conclusion
It is feasible to apply the NIH criteria retrospectively. Most patients can be diagnosed on clinical criteria without biopsy. Nearly 20% of pts diagnosed with cGVHD in the past did not fulfill the NIH criteria. Retrospective studies might show a delay in the onset of cGVHD compared to the expected timeframe of 4-6 months due to the requirement of diagnostic features not considered in the past and the category of late acute GVHD. Overlap and moderate cGVHD were the most common categories. A positive prognostic effect of cGVHD could not be detected for overall survival in our patient group.

Disclosures:
No relevant conflicts of interest to declare.