Haploidentical Peripheral Blood Stem Cell Transplantation after Treosulfan-Based Conditioning and Rapamycin GvHD Prophylaxis in Hodgkin Lymphoma
Authors: Morelli Mara , Lazzari Lorenzo , Lorentino Francesca , Greco Raffaella , Giglio Fabio , Assanelli Andrea Angelo , Marcatti Magda , Dalto Serena Camilla , Marktel Sarah , Milani Raffaella , Tassara Michela Giulia , Lupo Stanghellini Maria Teresa , Bonini Chiara , Peccatori Jacopo , Ciceri Fabio 
Published: October 2019

Abstract
Patients with advanced refractory Hodgkin Lymphoma (HL) may obtain long-term cure from haploidentical SCT. We experienced a package of haploidentical peripheral blood stem cell transplantation after Treosulfan-based conditioning and Rapamycin GvHD prophylaxis.
Between July 1999 and June 2016, 57 patients with classical relapsed/refractory Hodgkin Lymphoma underwent an allogeneic stem cell transplantation (alloSCT) at san Raffaele Scientific Institute in Milan (Italy). Eleven patients received a matched related donor alloSCT, 7 patients received a matched unrelated donor alloSCT, one patient underwent a double cord blood transplant and 38 patients, lacking identical related or unrelated donor, received an haploidentical transplant (haploSCT); 32 out of 38 patients underwent an unmanipulated peripheral blood stem cell transplant.
This retrospective study analyzes the outcome of these 32 patients allografted after a Treosulfan based conditioning and a backbone GvHD prophylaxis with the mTOR inhibitor Rapamycin.
Median age at alloSCT was 30 years; twenty patients (62,5%) had a primary refractory disease. Median number of previous lines before haploSCT was 4 (range 2-8); thirty patients (94%) received at least one or more autologous stem cell transplant and 12 of them were considered in an auto-allo program. Median time from diagnosis to haploSCT were 30 months (range 8-146).
At haploSCT after receiving the last salvage treatment, 10 patients were in complete remission (CR), 6 were in partial remission (PR) and 16 patients had progressive disease (PD).
A combination of Melfalan or Thiotepa or TBI4Gy to Treosulfan mieloablative conditioning regimens (MAC) were used in 16 (50%) patients; the others received a Treosulfan-alone based reduced intensity conditioning regimen (RIC). GvHD prophylaxis consisted of in vivo T cell depletion with pre transplant anti-Thymocyte Globulin (ATG) in 19 patient and of post transplant Cyclophosphamide (PT-Cy) in 13 patients; all patients received also Mycophenolate Mofetil till day + 30 and Rapamycin till day + 90. Median numbers of infused CD34+/Kg were 5,4 x 10^6 (range 5-5,8) and median numbers of infused CD3+/Kg were 2.34 x 10^8 (range 1.00-4.76).
Median follow up was 46 months (range 1-109); two and 4 years Overall survival (OS) was 52% and 48% respectively, Progression Free Survival (PFS) and Relapse Incidence (RI) were 29% and 59% at both two and four years. Transplant related mortality was 9.5% at 100 days, 13% at 1 year and for the entire follow-up. The 100-day Cumulative Incidence (CI) of grade ≥ 2 and grade ≥ 3 aGvHD were 31% and 19% respectively; CI of cGvHD was 38% and CI of moderate-severe cGvHD was 27% at both a 2 and 4 years.
No difference in OS, PFS, RI were found if patients were stratified according to disease status at transplant or according to the use of ATG or PT-Cy. CI of cGvHD and CI of moderate-severe cGvHD were significantly better after RIC regimens vs MAC ones (p value 0.01 and 0.001 respectively), but no difference were found between the two groups in term of OS, PFS and RI.
Twelve out of twenty-two patients with active disease at haploSCT achieved a CR after transplantation and median time from aploSCT to CR was 3 months (range 2-6); six of them (4 PD and 2 PR at transplant) achieved and maintained a CR for the entire follow-up without the need for other post transplant treatment.
Unmanipulated peripheral blood haploSCT after Treosulfan based conditioning regimen and GvHD prophylaxis with Rapamycin is feasible, even in heavily pretreated patients and with active disease, with acceptable toxicities. Intensification of conditioning increased the toxicities. Disease relapse or progression was the major cause of treatment failure in our series, but 22 patients (69%) had detectable disease at the time of transplant. Six out of those very poor prognosis patients (28%) achieved a long term CR. Hodgkin Lymphoma is characterized by high mTOR activity, and Rapamycin is known to inhibit in vitro and in vivo cell proliferation and to induce apoptosis in Lymphoma cells. Rapamycin in these patients could have played an important role in disease control in immediate post transplant phase by increasing the apoptotic effect of chemotherapeutic agents, until the onset of the Graft versus Lymphoma effect.

Disclosures
Bonini: Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Ciceri:MolMed SpA: Consultancy.