Primed-GCSF BMT Following Reduced Intensity Conditioning Regimen (RIC) for Patients (pts) with Poor-Prognosis, Heavily Pre-Treated, Hodgkin's Disease (HD).
Authors: Calixto Rodolfo , Ostronoff Mauricio , Ostronoff Fabiana , Manso Djenane , Maior ANA Patricia Souto , Sucupira Alexandre , Florencio Rodrigo , Martins Monique , Botelho Luis Fabio , Coutinho Mariana 
Published: October 2019

Abstract
Abstract 1312
Poor prognosis factors in HD include chemotherapy refractoriness, early relapse (especially in areas that has been previously irradiated), bulky disease and bone marrow or visceral involvement. Pts with poor prognosis resistant disease have been treated with RIC allo-SCT or tandem auto-SCT followed by RIC allo-SCT.
Primed-GCSF BMT has shown to accelerate the neutrophil recovery and decrease the incidence of chronic GVHD in comparison to PBSCT without affecting the graft-versus-lymphoma (GVL) effect.
From December 2004 to January 2010 we treated 18 pts with chemo and radiotherapy resistant HD with G-CSF-primed allo-BMT. Initial staging was II-B in 6 pts and III-B 7 pts, IV-B 5 pts. The median time between diagnosis of HD and the transplant was 19 months (9 – 38 mo). Ten out of the 18 pts had chemotherapy-refractory disease, 6 had early relapses (< 12 mo) in previously irradiated areas and 2 had visceral relapse (pulmonary). Prior to transplant, 39% of the pts had been treated with 2 chemotherapy regimens prior to respond and 61% had been treated with 3 or more. Ten pts had received prior radiation therapy and all patients with bulky disease were previously irradiated.
Thirteen pts received one auto-SCT prior to the allo-SCT for cytoreduction (6 chemo sensitive and 07 chemo resistant). The toxicity for tandem transplant, auto-SCT followed by RIC allo-BMT, for the remaining 5 refractory pts was thought to be excessively high and therefore they went straight to allo-BMT.
The protocol was approved by our institutional review board and informed consent was obtained from each pt and donor and or their guardians.
Conditioning regimen for the auto-SCT consisted of Cyclophosphamide 1500 mg/m2 (D-6 to D-3), Etoposide 400 mg/m2 (D-6 to D-3) and Carmustin 150 mg/m2 (D-6 to D-4). This regimen was well tolerated by all pts undergoing tandem-SCT.
RIC regimen for the allogeneic G-CSF-primed BMT consisted of Busulfan 4mg/kg/day (D-5 and D-4) and fludarabine 30 mg/m2/day (D-7 to D-2) and Cyclophophamide 350mg/m2/day (D-4 to D-2). GVHD prophylaxis consisted of CSA 5mg/kg/day orally from day -1 to day +90 and MMF 45mg/kg/day orally until day +30.
The donors received G-CSF 5 μg/kg/d subcutaneously for five days (D–4 to D0) prior to harvest the bone marrow. The median CD34+, CD3+ and CD8+ cell count infused were respectively 3.1 × 106 cells/kg (1.9 - 8.5 × 106/kg), 42 × 106 (28 – 59 × 106 cells/kg) and 11 × 106 cells/kg (6 - 31 × 106).
All pts received G-CSF 10 micrograms/kg/day SC from D0 until neutrophil engraftment. The median time for neutrophil and platelet to recover was respectively 5 days (3 – 12 d) and 6 days (4 – 13 d). All pts had complete chimerism on day +30 and there were no graft rejections.
One pt had CMV reactivation which was treated with gancyclovir. Treatment related mortality at D+365 after the allo-BMT was 22% (4 out of 18 pts); three pts died of acute GVHD on D+49, D+88, D+110 and one pt died of chronic GVHD of the lung on D+198.
Grade ≥ II acute GVHD occurred in 9/18 pts (50%) and grade III-IV in 3/18 (17%). Extensive chronic GVHD occurred in 2/18 pts (11%).
There were 9 deaths (50%); causes of death included acute GVHD in 3 pts, pulmonary GVHD in one pt and relapse in 4 pts at 2, 6, 9 and 17 months after the allo-BMT. The overall survival and disease free survival were respectively 50% and 45% with a median follow up of 27 months (range, 8 – 48 months). One patient relapsed on day+220; this pt maintained full donor chimerism and had no evidence of chronic GVHD. DLI was attempted without success. Disease free survival for pts with refractory disease (10 pts) was 40% (8, 13, 27, 31 months).
Primed-BMT after RIC for patients with poor prognosis HD resistant to chemo and/ or radiotherapy may be potential treatment, offering lower toxicity, rapid neutrophil engraftment and low incidence of chronic GVHD without affecting the GVL effect.

Disclosures:
No relevant conflicts of interest to declare.