A Multicentre Retrospective UK Study Detailing Onset Of Graft Verus Host Disease, Responses To Treatment and Outcome After Donor Lymphocyte Infusion Following Haemopoietic Stem Cell Transpantation: Rates Of GVHD Are High But Death From GVHD Infrequent

Donor lymphocyte infusions (DLI) are frequently used following haemopoietic stem cell transplant (HSCT) in patients with a high risk of relapse. Limited data are available on the characteristics of GVHD in this setting. The aim of this study is to investigate the NIH type, severity, treatment and response rates of GVHD following DLI.

Consecutive patients receiving DLI at 4 transplantation centres in the UK were identified since 2006. Data were collected retrospectively to include diagnosis, date of transplant, dates and doses of DLI, onset of GVHD, treatment of GVHD, follow up (FU) and outcome.

58 patients were identified having received DLI. The mean age at HSCT was 55yrs (median 45, range 20-70). Haematological malignancies were AML in 22, MDS in 9, CML in 7, myeloma in 5, CLL in 5, NHL in 3 and other in 7. 33 received matched related and 25 unrelated donor transplants. The reason cited for DLI was pre-emptive (mixed chimerism) in 30, therapeutic in 28 (relapse in 18, molecular relapse in 6, cytogenetic abnormality in 3 and consolidation in 1). DLI was given at a mean of 14 months after HSCT (median 7, range 1-65). DLI dose ranged from 1x10⁵–1x10⁷ CD3+ cellskg^-1. The number of doses ranged from 1-8, mean 2.3, median 2.

43 patients had GVHD after DLI (acute in 16, chronic in 26 and overlap in1). In aGVHD skin was the most common organ involved in 13/16 patients, followed by liver in 7, and gut in 6. 9/16 had single organ involvement (7 skin only, 2 liver only). 3 patients had skin and gut and 4 skin, gut and liver. In 6 patients this was severe (grade III-IV aGVHD). Of the 27 with cGVHD the most common organ involved in decreasing order was skin (n=20), oral (n=16), liver (n=9), eye (n=6), gut (n=4) and lung (n=1). 9 patients had single organ involvement (skin only in 6, oral 2, eye 1). 12 patients had 2, 2 had 3, 2 had 4 and 2 had five organs involved. 8 patients had cGVHD recorded as severe. The mean time between first DLI doses and development of aGVHD was 2 months (median 1, range 1-5 months) and 5.7months (median 3, range 1-28) in cGVHD.

First treatment of aGVHD was oral prednisolone in all 16 patients: first treatment response was CR in 4/16, relapse in 4 and progressive GVHD in 8. 5 died (2 from relapse, 2 from aGVHD and 1 from pneumonia). 5 with progressive GVHD received a 2nd line therapy (ECP in 3, tacrolimus in 1 & MMF in 1). 2 patients had a CR, 1 patient relapsed and died, 1 has ongoing mild GVHD and the other had 3^rd line therapy with ECP and a PR. The 1^st treatment in cGVHD was oral prednisolone in 16/27 (prednisolone alone in 12, plus CyA in 2, tacrolimus in 1, MMF in 1). 9 received topical steroids only, 1 received MMF and 1 rituximab. 16/27 patients had a CR to first line therapy, 1 died of severe lung GVHD and 1 relapsed. 9 received a 2^nd line therapy (ECP in 4, MMF in 3, imatinib in 1 and infliximab in 1). 1 had CR, 7 had PR and 1 relapsed. 4 had a 3^rd line therapy (ECP in 2 and MMF in 2) of which 1 had CR and 3 PR. I further patient had a 4th therapy with ECP and a PR. Of 8 patients with severe cGVHD 1 had 1 therapy (and died), 4 had 2, 2 had 3 and 1 had 4 therapies: 7/8 are alive, 4 in remission with GVHD, 2 in remission without GVHD and 1 relapsed.

Mean FU for cohort is 51.7 months (median 45, range 5-124) post HSCT. 35 are in remission, 11 of whom are receiving treatment for GVHD (4 with severe cGVHD). 18 patients relapsed (7 are receiving treatment and 11 died). In total 16/58 died and causes were relapse (11), severe GVHD (3, 2x aGVHD,1x cGVHD), ruptured aortic aneurysm (1) and pneumonia (1). 7/30 (23%) patients receiving DLI for mixed chimerism died compared to 9/18 (50%) receiving DLI for relapse. Overall survival in those developing aGVHD and cGVHD was 63% and 74% respectively compared to 12/15 (80%) in those without GVHD. Death from relapse was similar in those with and without GVHD post DLI at 20% and 26% respectively and death rates in those with severe GVHD do not appear higher.

We report on 58 patients receiving DLI after HSCT. 74% developed GVHD which was severe in 24%. In the majority of patients developing GVHD after DLI successful treatment may be achieved with increased immunosuppression. 39% of patients received second line therapy for GVHD most commonly ECP. 21% received a third line therapy. 16/58 patients have died (28%) including 3 (5%) of GVHD. The most common cause of death was relapse in 19%. In summary patients develop both aGVHD and cGVHD post DLI and may require consecutive therapies but mortality from GVHD is infrequent.