Intensification Of Treosulfan and Fludarabine-Based Conditioning With 4 Gy TBI For Allogeneic Stem Cell Transplantation In Patients With Hematological Malignancies
Authors: Giglio Fabio , Brambilla Corrado Zuanelli , Lorentino Francesca , Piemontese Simona , Crucitti Lara , Levati Giorgia , Greco Raffaella , Morelli Mara , Messina Carlo , Forcina Alessandra , Stanghellini Maria Teresa Lupo , Vago Luca , Marktel Sarah , Marcatti Magda , Assanelli Andrea , Corti Consuelo , Bernardi Massimo , Bonini Chiara , Ciceri Fabio , Peccatori Jacopo 
Published: October 2019

Abstract

Background
Hematopoietic stem cell transplantation (HSCT) is so far the only potentially curative option for patients with aggressive hematological malignancies. Since many patients cannot find a suitable HLA-identical (related or unrelated) donor, it is essential to analyze the safety of alternative graft sources, such as haploidentical donors. The use of reduced-intensity conditioning regimens in patients with an advanced disease did not improve the outcome because of a higher incidence of relapse. Here we present an interim analysis of this phase II prospective clinical trial that investigates a new conditioning regimen for allogeneic HSCT based on a well established one (Fludarabine and Treosulfan) intensified adding 4 Gy TBI with the aim of maintaining an acceptable toxicity profile while reducing the incidence of relapse in high-risk patients (TrRaMM4Gy study, Eudract 2011-001534-42).

Patients and Methods
Ninety-six patients underwent allogeneic HSCT for AML (n=46), ALL (n=13), acute biphenotypic leukaemia (n=2), HD (n=8), NHL (n=7), MDS (n=6), Myelofibrosis (n=5), MM (n=4), CML (n=2), CMML (n=2) or CLL (n=1). The median age was 45 years (range 17-67). At the time of the transplantation most patients (n=76) were in advanced disease phase, while the remaining 20 patients were in early phase. Twenty-eight patients were enrolled for relapse after a previous allogeneic HSCT. Median time from diagnosis to transplantation was 443 days (range 56-5249). Median comorbodity index score (according to Sorror criteria) was 2 (range: 0-8). Sixty-two patients received the graft from haploidentical donors, 17 from MUD, 14 from HLA-identical sibling and 3 patients from a single cord blood unit. Median number of CD34+ and CD3+ cells/kg were 6.46 millions and 241 millions respectively. The conditioning regimen included Treosulfan (14 g/m2 for 3 days), Fludarabine (30 mg/m2 for 5 days) and 4 Gy TBI split in 2 fractions. Patients receiving HSCT from haploidentical donor (arm A) were also treated with ATG-Fresenius (10 mg/kg for 3 days) and Rituximab (200 mg/m2 in single dose), patients receiving HSCT from HLA-identical sibling, MUD or single cord blood unit and in early disease status (arm B) were also treated with ATG-Fresenius (5 mg/kg for 3 days) and Rituximab (200 mg/m2 in single dose), while patients receiving HSCT from HLA-identical sibling, MUD or single cord blood unit and in advanced disease status (arm C) did not receive any ATG or Rituximab. GvHD prophylaxis consisted of Sirolimus (target concentration 8-15 ng/ml, till day +60) and Mycophenolate Mofetil (10 mg/kg tid till day +30).

Results
Neutrophils engraftment was reported at a median time of 17 days (range: 9-46) in all 91 evaluable patients; five patients died of transplant-related causes (n=4) or disease progression (n=1) before day +15. Platelets engraftment occurred after a median time of 17 days (range: 4-153) in 75 patients (82%). At the first marrow evaluation on day +30 all the evaluable patients showed full donor chimerism, 77 patients (90%) were in complete remission and 9 were in stable disease or progression. After a median follow-up of 425 days, cumulative incidence of grade 2-4 and 3-4 aGvHD were 40% and 26% respectively. Cumulative incidence of moderate or severe cGvHD (according to NIH criteria) was 57%. Cumulative incidence of NRM at day +100 and +365 were 23% and 36% respectively; cumulative incidence of relapse at day +365 was 33%. Overall survival and progression-free survival 1 year after HSCT were 51% and 43% respectively. EBV reactivation occurred in 7 patients, but no PTLD was observed.

Conclusions
The new conditioning regimen we investigated proved to be feasible in this high-risk population. We did not observe any major difference in terms of NRM and aGvHD compared to the data from our previous trial (TrRaMM, Eudract 2007-5477-54) with similar inclusion criteria and patient characteristics, but a reduced-intensity conditioning regimen based on Treosulfan and Fludarabine. Interestingly, we observed a trend of lower relapse incidence, resulting in a better OS and PFS. The low toxicity profile of Treosulfan and Fludarabine should be considered as a myeloablative platform for further intensification; more studies are warranted in order to find the association for a conditioning regimen endowed with a low toxicity profile but still a strong anti-tumor activity.

Disclosures:
Bonini: MolMed SpA: Consultancy.