Favorable Outcome in Patients with Lymphoid Malignancies Following Allogeneic Stem Cell Transplantation Using Fludarabine and Treosulfan As the Preparative Regimen
Authors: Yerushalmi Ronit , Shimoni Avichai , Shem-Tov Noga , Volchek Yulia , Avigdor Abraham , Nagler Arnon 
Published: October 2019

Abstract
Abstract 1934
Allogeneic stem cell transplantation (SCT) is potentially a curative therapy for patients (pts) with lymphoid malignancies. A myeloablative preparative regimen is not always feasible due to patients' age or medical condition. Treosulfan is a pro-drug of a bi-functional alkylating agent with intensive myelosuppressive as well as immunosuppressive properties and a relatively favorable toxicity profile. The combination of fludarabine and treosulfan (FT) has been introduced over the last few years as a relatively dose-intensive, low toxicity regimen. It was predominantly explored in pts with myeloid malignancies and there is only limited data on the expected outcomes of this regimen in pts with lymphoid malignancies. We studied 43 pts with various lymphoid malignancies including diffuse large B-cell lymphoma (DLBCL, n=13), Hodgkin lymphoma (HL, n=8), T-cell lymphomas (n= 10), follicular or mantle cell lymphoma (n=8) and chronic lymphocytic leukemia with Richter's transformation (CLL, n=4). The median age was 57 (range, 23–70) years, 24 females and 19 males. 6 pts had a Karnofsky score ≤80. 24 pts had chemo-sensitive disease at SCT (CR-16, PR-8) and 19 pts had chemo-refractory disease (SD-7, PD-12). 27 pts had a prior autologous SCT. The donor was an HLA-matched sibling (n= 24) or unrelated (n=19). 42 pts were given peripheral blood stem cells and one had a bone marrow graft. The median graft composition was 8×10e6 CD34+cells/kg (range, 2.9–12) and 3.3×10e8 CD3+cell/kg (range, 1–10.7). 11 patients were given treosulfan at a total dose of 30 g/m2 and 32 a dose of 36 g/m2. The median follow up of surviving pts is 13 months (range, 1–33 months). The median time to neutrophil and platelet engraftment was 13 days (range, 10–20 range) and 14 days (range, 11–30), respectively. 11 pts had acute GVHD (cumulative incidence 27%), graded in 2 of them as grade III-IV (5%). 11 pts had chronic GVHD (cumulative incidence 46%), 6 of them graded moderate to severe (28%). Ten patients had non-relapse mortality (NRM), 2 died of infections, 3 of GVHD (2 acute, 1 chronic), 5 of organ toxicities. The cumulative incidence of NRM was 29% (95%CI 16–51%). 13 patients achieved CR after SCT, 13 had continued CR and 7 did not achieve a response. Ten are not evaluable (7 early NRM, 3 pts are still too early after SCT). 13 pts progressed after SCT, cumulative incidence, 32% (95CI, 21–51). Five of them died, 2-year cumulative incidence of relapse mortality 12% (95%CI. 5–30%). In all, currently, 28 pts are alive and 20 are progression-free. The estimated 2-year overall survival (OS) rate is 59% (95% CI.40–77%) and the 2-year progression-free survival (PFS) is 39% (95% CI 21–57%). The 2-year OS for pts with chemo-sensitive and chemo-refractory disease was 64% (95%CI 39–88) and 49% (95%CI, 1–65), respectively (p=NS). The 2- years PFS was 51% (95%CI 26–76) and 23% (95%CI, 1–44), respectively (p=0.01). Pts with DLBCL and transformed CLL (poor-risk histologies) had a PFS of 20% (95%CI 0–41) compared with pts with the other histologies (HL, T-cell, follicular and mantle cell lymphomas) who had a PFS of 58% (95%CI, 37–70, p=0.05). In a multivariate analysis a low Karnofsky score (70–80 Vs 90–100) [HR 2.5 (0.9–6.8) p=0.07], chemo-refractory disease [HR 3.0 (1.2–7.5), p=0.02], and poor-risk histology as defined above [HR 2.5 (1.0–5.9), p=0.04] were predictive for shortened PFS. An unrelated donor (HR 5.1, p=0.05) and a lower Karnofsky score (HR 8.4 p=0.01) were predictive of NRM. Chemo-refractory disease (HR 12.7 p=0.001) and poor-risk histology (HR 3.8 p=0.06) predicted relapse. In conclusion, the combination of fludarabine and treosulfan is a promising preparative regimen for allogeneic SCT in pts with lymphoid malignancies. Similarly to the experience in myeloid malignancies, NRM rates are reasonable, considering the relatively heavily pretreated and high-risk pt group (44% chemo-refractory, 63% with a prior autologous SCT). This is also a dose intense regimen as reflected by the relatively low relapse rate. Outcome was favorable in pts with chemo-sensitive disease, but a subset of pts with chemo-refractory disease at SCT could also be salvaged. This regimen merits further study in larger comparative studies.

Disclosures:
Nagler: medac, germany: Research Funding.