Chronic Graft-Versus-Host Disease: Lessons From a Randomized Trial on GvHD Prophylaxis with or without Anti-T-Cell Globulin ATG-Fresenius (ATG-F) In Allogeneic Hematopoietic Cell Transplantation (HSCT) From Matched Unrelated Donors

Chronic GvHD (cGvHD) is the leading late complication after allogeneic HSCT. Most previous randomized studies in GvHD prophylaxis failed to demonstrate reduced incidence and severity of cGvHD, and shorter time to discontinuation of immunosuppressive therapy (IST).

We previously reported that addition of ATG-F to standard cyclosporine, methotrexate GvHD prophylaxis (control group) significantly reduced severe acute and chronic GvHD (Finke et al., Lancet Oncology, 2009). Here we present final data and unpublished results on cGvHD with extended follow-up [median of 3 (25%-quartile 2.5, 75%-quartile 3.9) years] on 201 patients with median age of 40 (range 18–60) years, transplanted between 2003 and 2007, with AML (n=101), MDS (n=10), ALL (n=70), CML (n=17), OMF (n=3) in early (1^st CR or MDS-RA, n=107), or advanced status of disease (all other, n=94).

With extended follow-up the cumulative incidence (CI) of extensive cGvHD after three years was 12.2% in the ATG-F group versus 45.0% in the control group (p<0.0001) (Figure1) [CI of limited + extensive was 30.0% and 60.0% in the ATG-F versus control, respectively, p<0.0001]. CIs were reduced in all main cGvHD target organs: skin [3-year CI, 5.6% to 27.0%; (hazard ratio (HR) =0.18, p=0.0006)], eyes [3-year CI, 2.2% to 20.7%; HR =0.10, p=0.0025)], mouth [3-year CI, 4.4% to 18.8%; HR =0.24, p=0.013)], lung [3-year CI, 3.3% to 16.3%; HR =0.17 p=0.006)], and liver [3-year CI, 16.7% to 33.8%; HR =0.43, p=0.009]. Chronic GvHD decreased relapse rate resulting in HR of 0.49 (p=0.037), 3-year CI of relapse was 32.6% in the ATG-F and 28.2% in the control group (HR=1.21, p=0.47). Extensive cGvHD increased non-relapse mortality (NRM) rate resulting in a HR of 2.1 (p=0.075), 3-year CI of NRM was 19.4% in the ATG-F and 33.5% in the control group (HR=0.68, p=0.47). The 3-year CI of late bacterial infection (post Day+100) was 26.3% and 39.9% in the ATG-F versus control, respectively (HR=0.65, p=0.12). Cox regression analyses on risk factors for developing extensive cGvHD adjusted for treatment arm and acute GvHD (time dependent) found two factors associated with increased extensive cGvHD risk: donor age more than 40 years (HR= 2.02, p=0.025) and disease type [HRs=3.90, 1.56 and 2.62 for patients with MDS, ALL and CML/OMF as compared to AML, respectively; p=0.04]. Overall survival after three years was 55.2% in the ATG-F and 43.3% in the control group (HR=0.84, p=0.39). The HR for receiving IST was 0.58, p<0.00001, and the HR for stopping IST was 1.37, p=0.006 (ATG-F versus control, respectively). At 3 years, the probability of being alive without IST was 46.9% and 18.1% and that of being alive with IST was 8.4% and 26.1 % in the ATG-F versus control, respectively.

The addition of ATG-F to standard cyclosporine, methotrexate GvHD prophylaxis significantly reduces the incidence and severity of cGvHD, and the risk of receiving IST without increasing relapse rate. Although the 3-year CI of NRM (19.4% in the ATG-F and 33.5% in the control group, p=0.18) are still non-significantly different, these data demonstrate that ATG-F prophylaxis decreases cGvHD morbidity and may thus provide a long-term survival advantage.

Figure:

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Extensive cGvHD Treatment effect estimated from Cox model adjusted for status of disease and source of stem cells Hazard ratio (ATG vs. Control)=0.20, 95%-CI [0.10,0.39], p<0.0001

Figure:

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Extensive cGvHD Treatment effect estimated from Cox model adjusted for status of disease and source of stem cells Hazard ratio (ATG vs. Control)=0.20, 95%-CI [0.10,0.39], p<0.0001

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Bethge:Fresenius Biothech GmbH: Lecture remuneration. Finke:Fresenius Biothech GmbH: Research Funding.