Favorable Outcome For Patients With Lymphoid Malignancies Following Allogeneic Stem Cell Transplantation Using Fludarabine Treosulfan, Compared With Other Reduced Intensity Conditioning Regimen
Authors: Yerushalmi Ronit , Shem-Tov Noga , Volchek Yulia , Danylesko Ivetta , Avigdor Abraham , Nagler Arnon , Shimoni Avichai 
Published: October 2019

Abstract
Allogeneic stem cell transplantation (SCT) is potentially a curative therapy for patients (pts) with lymphoid malignancies. A myeloablative preparative regimen is often not feasible in these pts due to advanced age, medical condition or extensive prior therapy leading to high non-relapse mortality (NRM) rates. Reduced intensity condition (RIC) allows SCT by reducing NRM but may be associated with increased relapse rate, especially in pts with advanced malignancy. Novel regimens with intensive anti malignancy activity but limited toxicity will be of benefit. The combination of fludarabine and treosulfan (FT) is a dose intense reduced toxicity regimen. It has been predominantly explored in myeloid malignancies but there is only limited data on the relative outcomes of this regimen in pts with lymphoid malignancies in comparison to more commonly used RIC regimens.
We evaluated the outcome of 144 pts with lymphoid malignancies given allogeneic SCT with FT (30-36 gr/m2, n=50), fludarabine and intravenous busulfan (6.4 mg/m2, FB2, n=38) or fludarabine melphalan (100-140 mg/m2, FM, n=56). 115 (80%) had non Hodgkin lymphoma of various histologies and 29 (20%) pts had Hodgkin lymphoma. Pts with CLL, Burkitt and lymphoblastic lymphoma were excluded. The median age was 52 (16-69) years, 90 male and 54 female. 26 pts (18%) had more than 3 lines of prior chemotherapy and 87 (60%) had a prior autologous SCT. 13 pts (9%) had a comorbidity index (HCT-CI) ≥3. 69 pts (48%) had chemo-sensitive disease at SCT and 75 (52%) had chemo refractory disease. The donor was an HLA-matched sibling (n= 83, 58%) or matched unrelated donor (n=61, 42%). The FT and FB2 groups included more pts with a prior autologous SCT than the FM group, 76%, 79% and 34%, respectively (p=0.001). There were no other differences between the 3 treatment groups in pt's characteristics. With a median follow up of 39 months (4-149), 58 pts are alive and 86 died, 52 of NRM and 34 of relapse. The 3 year overall survival (OS) rate for the whole group was 42% (32-49%). Disease status at SCT was the most significant predictor of OS. Pts with chemo sensitive disease had OS of 62% (50-75%) whereas pts with chemo refractory disease had OS of 20% (10-30%, p<0.001). The 3 year OS was 54% (36-72), 43% (27-59) and 29% (17-40) after FT, FB2 and FM, respectively (p=0.02). Multivariate analysis (MVA) identified age>50 (HR=2.0, 1.1-3.8, p=0.03), HCT-CI≥3 (HR=6.0, 2.8-12.6, p<0.001), FM (HR=3.1, 1.3-7.6, p=0.01) and chemo refractory disease (HR=3.5, 2.0-6.2, p<0.001) to be associated with shortened OS. The correlation between OS and conditioning regimen was dependant on disease status at SCT. There was no significant difference among the regimens in pts with chemo sensitive disease, 3-year OS of 67% (45-87), 74% (54-94) and 48% (26-69) after FT, FB2 and FM, respectively (p=0.28). However, among pts with chemo refractory disease there was an advantage for FT. OS was 34% (3-65), 11% (0-25) and 17% (2-25), respectively (p=0.03 for FT vs others). MVA limited to pts with chemo refractory disease showed HCT-CI≥3 (HR=5.0, 1.6-16.1, p=0.007) and treatment with FT (HR-0.4, 0.12-1.1, p=0.07) to be significant factors in this subgroup. The 3 year cumulative incidence of NRM was 24% (14-41%), 22% (12-40%) and 54% (42-68%) after FT, FB2 and FM, respectively (p=0.004). MVA for NRM identified age>50 (HR=2.1, 0.9-4.4, p=0.07), HCT-CI≥3 (HR=6.3, 2.6-15.7, p=0.001), FM (HR=5.1, 1.6-16.3, p=0.007) and chemo refractory disease (HR=2.0, 1-4.0, p=0.04) as independent adverse factors. A sibling donor had a protective effect (HR=0.5, 0.2-0.9, p=0.03). Relapse mortality was 22% (11-44), 35% (23-55) and 18% (11-31), respectively (p=0.4). MVA identified HCT-CI≥3 (HR=4.2, 1.1-16.7, p=0.04) chemo refractory disease (HR=13.9, 4.7-41.9, p<0.001) and prior autologus transplant (HR=5.1, 1.1-23.5, p=0.03) as adverse factors.
In conclusion, FT is a promising preparative regimen for allogeneic SCT in pts with lymphoid malignancies. Dose intensity is important in lymphoid malignancies. FT and FM are both dose intensive cyto-reductive regimens as reflected by lower relapse rates than FB2. FT is associated with lower NRM than FM, in similarity to the known favorable profile of FB2. These effects result in a more favorable OS with FT, in particular in advanced disease. A subset of pts with chemo refractory disease could also be salvaged. This regimen merits further study in larger comparative studies.

Disclosures:
No relevant conflicts of interest to declare.