Table 4.

Primary Therapy Trials in Acute GVHD

Treatment	N	Design	Results and Conclusions	Ref
Prednisone* 2mg/kg	443	Retrospective single center. Era: 1990–1999; 40% cohort age < 20 yrs.	Day 28 CR/PR 35%/20%. 1-yr OS 53% (95% CI, 48%–58%). Lower GI ± other organ had worse response. Better OS: age <20, T-replete, Gd I–II at onset, related or matched unrelated donor.	[20]
Prednisone* 1 mg/kg v 2 mg/kg	733	Retrospective single center. Compared different prednisone starting doses. Era: 2000–2005.	For grades II, GVHD control or mortality not compromised at 1 mg/kg v 2 mg/kg. Lower fungal infection rates and duration of hospitalization for 1 mg/kg. For grades III/IV, small numbers precluded definitive conclusions.	[21]
Methylprednisolone 2 mg/kg v 10 mg/kg	95	Phase III, multicenter, T- replete MSD BMT. Crossover after 5 days to 10 mg/kg for non-responders at 2 mg/kg.	Compared to 2 mg/kg, 10 mg/kg did not improve response rates (71% v 68%), TRM, OS, rates of CMV infection, or evolution to grade III-IV aGVHD. TRM 46% among the 55% of non-responders to 5 days of 2 mg/kg who were rescued with MP10 mg/kg versus 16% among responders (P=.007).	[26]
Methylprednisolone 2 mg/kg v 5 mg/kg	211	Phase III multicenter. Eligibility: grade I–IV. Day 5 non-responders (N=61) randomized to MP 5 mg/kg or 5 mg/kg + rATG	Day 5 CR rate 71% and patients tapered MP from D6. 5 yr TRM cumulative incidence 27% v 49% (P=.009), and OS 53% v 35% (P=.007) for responders and nonresponders respectively. No significant difference in response, TRM, OS between non-ATG and ATG groups.	[33]
Prednisone* 1 mg/kg + orBec® v placebo	129	Phase III, multicenter. Eligibility: grade IIa (anorexia, vomiting, diarrhea < 1L). Randomized (1:1) to 10 days prednisone + 50 days of oral BDP or placebo. Prednisone rapidly tapered from Day 11.	Among patients eligible for prednisone taper at study day 10, the risk of GVHD- treatment failure was lower in BDP arm at day 80 (HR 0.38). Day 200 posttransplant mortality lower in BDP arm (HR 0.33, P = .03); mostly explained by 91% reduction in D200 mortality for recipients of unrelated and mismatched grafts (HR 0.09, P = .02). Survival benefit durable to 1 yr after randomization.	[24]
Prednisone* + Budesonide	22	Retrospective single center comparison of patients treated for GI GVHD with MP+BDE 3 mg TID to 19 MP-only historical controls.	CR 77% in BDE group v 42% in controls. Two of 8 CRs in controls developed recurrent GI aGVHD during MP taper vs 0 of 17 in BDE group who continued BDE during MP taper. No severe intestinal infections occurred.	[50]
Prednisone* 2 mg/kg + Anti-CD5 mAb v placebo	243	Phase III, single center, double blind trial.	Higher Day 28 CR rate (40% vs 25% P = .019) but similar Day 42 CR rate (44% vs 38%), and 1 yr survival (49% vs 45%) in anti-CD5 group v placebo; no long term benefit of anti-CD5 immunotoxin.	[12]
Methylprednisolone 60 mg/m2 v 40 mg/m2 + ATG	96	Phase III, single center, open label. Eligibility: REL/URD BMT. Intent-to-treat analysis.	Day 42 CR/PR 76% in both arms. More CMV infections and more pneumonitis in MP/ATG arm. EBV-PTLD uncommon in either arm. Equivalent OS at Day 100, 6 months, and 2 yrs. ATG should be reserved as second-line therapy.	[27]
Methylprednisolone 2mg/kg ± Infliximab	58	Phase III, single center, open- label	CR+PR rates 63% (MP) v 66% (infliximab + MP) were similar. Similar death rates in both arms; mainly due to GVHD and relapse.	[51]
Methylprednisolone 2mg/kg ± Etanercept	61	Retrospective single center analysis of Pilot (N=20) plus Phase II (N=41) prospective studies compared to contemporaneous MP only controls (N=99).	Etanercept resulted in more CRs (69% v 33%; P <.001); similar for REL and URD donors. Elevated plasma TNFR1 levels decreased significantly only in patients with CR	[29]
Methylprednisolone 2mg/kg ± Daclizumab v placebo	102	Phase III, multicenter, double- blinded.	Inferior 1-yr OS in combination arm (29% v 60%; P = .002) attributed partly to increased relapse/GVHD-related mortality. Study closed early: worse 100-day OS in combination arm (77% v 94%; P=.02). Day 42 CR/PR rates (53% v 51%)	[28]
Methylprednisolone 2mg/kg + Human MSCs	32	Phase II multicenter. Adults Randomization: 2 × 106 v 8.0 × 106 MSC/kg. GVHD grade at onset: II (21), III (8) and IV (3).	Day 28 CR/PR 77%/16%. Both MSC doses similarly effective. No infusional toxicities.	[52]
Methylprednisolone 2mg/kg + Human MSCs v placebo (1:1 ratio)	192	Phase III multicenter, double- blinded. Third party commercially prepared MSCs (Prochymal®, Osiris)	No difference in proportion of patients surviving at least 90 days that achieve a CR by day 28 (45% v 46%)	Osiris, press release
Methylprednisolone 2mg/kg + MMF or Etanercept or Pentostatin or Denileukin diftitox	180	Randomized phase II BMT CTN trial. MMF prophylaxis recipients (24%) were randomized to a non-MMF arm. At randomization: aGVHD was grade I–II (68%), III-IV (32%). Visceral organ involvement in 53%.	Day 28 CR rates, 9-month OS %, and C.I. severe infections were: etanercept 26%, 47%, 48%, MMF 60%, 64%, 44%, denileukin 53%, 49%, 62%, pentostatin 38%, 47%, 57%. MMF identified as most promising arm and will be compared to MP alone in phase III.	[30]

Abbreviations: ATG; antithymocyte globulin, BDE; budesonide, BDP; beclomethasone dipropionate, CI; confidence interval, CMV; cytomegalovirus, CR; complete response, GI; gastrointestinal, MSD; matched sibling donor, MP; methylprednisolone, OS; overall survival, PR; partial response, REL; related, TID; three times daily, TRM; treatment related mortality, URD; unrelated.