Primed-GCSF BMT After Reduced Intensity Conditioning (RIC) In Association with Rituximab for Patients (pts) with Refractory CD20+ Aggressive Lymphomas..
Authors: Calixto Rodolfo , Ostronoff Fabiana , Ostronoff Mauricio , Sucupira Alexandre , Manso Djenane , Maior ANA Patricia Souto , Florencio Rodrigo , Martins Monique , Botelho Luis Fabio , Coutinho Mariana 
Published: October 2019

Abstract
Abstract 1313
Auto-SCT for pts with refractory aggressive lymphomas is often not effective and most pts die of progression of disease. RIC has been used to treat these pts, but there is still a high relapse rate especially within the first year after the transplant. Administration of Rituximab during the first year of allo-BMT may help avoid relapse in the first year while allowing sufficient time for optimal GVL effect. Primed-GCSF BMT has shown to accelerate the neutrophil recovery and decrease the incidence of chronic GVHD when compared to PPBSCT without affecting the graft-versus-lymphoma (GVL) effect. From June/2005 to February/2010, 15 pts with aggressive CD20+ lymphomas, 12 of which with chemotherapy-refractory disease and 3 early relapses (less than 6 months after completing chemotherapy) underwent primed-GCSF BMT in association with Rituximab at our center. All pts had extensive disease at the time of transplant. The median age was 48 years (16 ..C 58 yrs), 9 were male. Histology included: 12 pts with DLBCL, 2 mantle zones and 1Richter syndrome. Initial staging included: stage II-B (4 cases), II-EB (3 cases), III-B (5 cases) and IV-B (3 cases). IPI score was low-intermediate in 2 pts, high-intermediate in 7 and high in 6. The median time from diagnosis to transplant was 18 months (8 ..C 34 mo). Eleven pts had been treated with chemotherapy regimen containing Rituximab prior to transplant, 6 of which were refractory to the treatment. Prior to transplant, 40% of the pts had been treated with 2 chemotherapy regimens prior to respond and 60% had been treated with 3 or more. Ten pts had received prior radiation therapy and all pts with bulky disease were previously irradiated. The pts were not eligible for myeloablative regimens due to age greater than 50 years (4 cases), serious infections during previous chemotherapies (4 cases), poor performance status with ECOG>=2 (7 cases). There were 3 pts who had chemo-sensitive disease and they all underwent auto-SCT with cyclophosfamide, etoposide and carmustin regimen 30 days prior to the allogeneic transplant. 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 consisted of Busulfan 4mg/kg/day (D-6 and D-5) and Fludarabine 30 mg/m2/day (from D-4 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 +120 and MMF 45mg/kg/day orally until day +30. The donors received G-CSF 5 μg/kg/d subcutaneously for five days (day ..C4 to day 0) prior to harvest the bone marrow. The median CD34+, CD3+ and CD8+ cell count infused were respectively 3.6×106 cells/kg (1.7 - 8.2 × 106), 37 × 106 (28 ..C 57 × 106) and 13 × 106 cells/kg (5 - 29 × 106). All pts received GCSF 10 micrograms/kg/day SC from day zero until neutrophil engraftment. The median time for neutrophil and platelet to recover was respectively 6 days (3 - 12) and 5 days (2 - 11). All pts had complete chimerism on day +30 and there were no graft rejections. Rituximab 375mg/m2 weekly for 4 weeks was administered for a total of 4 cycles (12 doses); the cycles started on days +60, +180, +300 after the allo-BMT. Three pts developed mild infusion reaction (tremor and rash). The hematological toxicity was low; grade II neutropenia occurred in 4/15 pts (27%) which was seen only after the forth dose of the cycle and lasted few days. One pt had CMV reactivation which was treated with Gancyclovir. Treatment related mortality at D+365 after the allo-BMT was 27%; three pts died of acute GVHD on D+45, D+78 and D+129 and one pt died of chronic GVHD of the lung on D+211. Grade ≥ II acute GVHD occurred in 7/15 pts (47%) and grade III-IV in 3/15 pts (20%). Extensive chronic GVHD occurred in 2/15 pts (13%). There were 7 deaths (47%); causes of death included acute GVHD in 3 pts, pulmonary GVHD in 1 pt and relapse in 3 pts at 6, 9 and 17 months after the allo-BMT. Disease free survival was 53% with median follow up of 31 months (6 - 48). Primed-BMT after RIC for patients with aggressive CD20+ lymphomas with chemo and/or radiotherapy refractory disease may be a potential treatment, offering lower toxicity, rapid neutrophil engraftment and low incidence of chronic GVHD and without affecting the GVL effect. Rituximab is well tolerated. The efficacy of this association (RIC + Rituximab) warrants further investigation.

Disclosures:
No relevant conflicts of interest to declare.