The increase from 2.5 to 5 mg/kg of rabbit anti-thymocyte-globulin dose in reduced intensity conditioning reduces acute and chronic GVHD for patients with myeloid malignancies undergoing allo-SCT

Abstract

We previously reported that reduced intensity conditioning (RIC) regimen with fludarabine, BU and 2.5 mg/kg of rabbit anti-thymocyte globulin (r-ATG) was effective but associated with a high rate of acute and chronic GVHD. Therefore, we increased the dose of r-ATG to 5 mg/kg. In this report, we analyzed 87 patients with AML or myelodysplastic syndrome (MDS) undergoing allo-SCT from an HLA-identical sibling donor from 2000 to 2010. RIC consisted of fludarabine, BU and r-ATG 2.5 mg/kg on 1 day (r-ATG1; n=53) or 2.5 mg/kg per day over 2 days (r-ATG2; n=22). Grade 2-4 acute GVHD incidence at day 100 was 30.2% and 8.8% in the r-ATG1 and r-ATG2 groups, respectively (P=0.038). Extensive chronic GVHD incidence was 60.4% and 12% in the r-ATG1 and r-ATG2 groups, respectively (P<0.001). The relapse incidences (RI) at 24 months were 18.9% and 28.5% in r-ATG1 and r-ATG2 groups, respectively (P=0.640). Overall and PFS were not different between the r-ATG1 and r-ATG2 groups. r-ATG dose at 5 mg/kg in the setting of RIC seems a good balance allowing GVHD prevention and antitumor effect with a remarkable reduction of GVHD incidence without an identical level of increased relapse rate.

The impact of graft-versus-host disease prophylaxis in reduced-intensity conditioning allogeneic stem cell transplant in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

“…In this particular setting, the comparison of ATG and CsA GVHD prophylaxis to prophylaxis not containing ATG showed that the use of ATG was not linked to a higher risk of relapse in patients with equivalent cytogenetic risks. Most of the patients in this study had received thymoglobulin at a dose <6 mg/kg, and these results are consistent with the previously reported preserved GVL effect in patients treated with relatively reduced doses of ATG, [12][13][14] in contrast with doses >10 mg/kg. 3 As previously described, 11,12 our study confirms a protective effect of ATG against chronic GVHD.…”

“…Indeed, two recent studies reported that GVHD prophylaxis with a reduced dose of ATG of 2.5 mg/kg versus 5 mg/kg in FluivBu2 RIC allogeneic HSCT with peripheral blood stem cells from matched related or unrelated donors was associated with an increased risk of acute and chronic GVHD. 13,14 Collectively, these data confirm that the optimal dose of thymoglobulin in the Flu-ivBu2 RIC regimen is about 5 mg/kg.…”

“…The impact of graft-versus-host disease prophylaxis in reduced-intensity conditioning allogeneic stem cell transplant in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation Marie Thérèse Rubio, 1,2,3 Myriam Labopin, 1,4 Didier Blaise, 5 Gerard Socié, 6 Rafael Rojas Contreras, 7 Patrice Chevallier, 8 Miguel A. Sanz, 9 Stéphane Vigouroux, 10 Anne Huynh, 11 Avichai Shimoni, 12 Claude-Eric Bulabois, 13 Nerea Caminos, 14 Lucía López-Corral, 15 Arnon Nagler, 12,4 * and Mohamad Mohty 1,2,3,4 * been poorly explored. While, the combination of CsA and a short course of methotrexate (MTX) after transplantation is considered as the gold standard for GVHD prophylaxis after conventional myeloablative allogeneic HSCT from HLA-identical siblings, 15,16 there is no consensus on the optimal preventive regimen for GVHD prophylaxis after RIC allogeneic HSCT.…”

“…3,11 It is now established that the effects of ATG in RIC are dose-dependent, 3 and that intermediate doses of thymoglobulin between 4 and 6 mg/kg seem to prevent GVHD optimally while sparing the GVL effect. [12][13][14] Apart from ATG, the impact of the post-transplant immunosuppression on transplant outcomes in allogeneic HSCT following RIC has October 19, 2014. Manuscript accepted March 6, 2015.…”

In patients older than 55 years with AML in first CR, should we search for a matched unrelated donor when an old sibling donor is available?

“…20 ATG did not impact the 2-year CI of relapse in our study, which differs from the CIBMTR one in regard to patients' age (only 55 years and older), stem cell source (only PBSC), disease type and status (only AML in CR1), and donor compatibility (only matched donor). However, our results are in accordance with earlier report by other smaller studies, [21][22][23] as well as to a recent publication by our group on 1250 adult patients with de novo AML in CR1 given PBSC from HLA-identical siblings after chemotherapy-based RIC regimen, where the use of ATG and the use of alemtuzumab were each associated with a lower risk of chronic GVHD, but a similar risk of relapse. 24 Because of the selection criteria (only patients 8/8 matched were considered), we were unable to assess the impact of mismatches on the risk of chronic GvHD and eventually NRM.…”