Long Term Results of Non-Myeloablative Stem Cell Transplantation in Non-Hodgkin’s Lymphomas: FLU150/MEL80 (Madrid Protocol).
Authors: Gayoso Jorge , Balsalobre Pascual , Tomás Jose F. , de la Serna Javier , Serrano David , Carrión Rafael , Buño Ismael , Gómez-Pineda Alfonso , Díez-Martín Jose L. 
Published: October 2019

Abstract
Introduction: Myeloablative allogeneic stem cell transplant has been reserved for long time to young well-fitted patients (pts) due to its high toxicity. Lately, different non-myeloablative (NMA) conditioning regimens have been employed to reduce this toxicity preserving the graft-vs-tumor effect (GVT). Here we present our experience in advanced lymphoma pts.
Patients & methods: Since year 2000, we used iv fludarabine 150 mg/m2 days −7 to −4 and iv melphalan 80 mg/m2 day −2 as NMA conditioning for heavily pretreated lymphoma pts, aged >55y or with comorbidities. GVHD prophylaxis consisted in cyclosporine and short course MTX. Stem cells were obtained from peripheral blood of an HLA-identical sibling donor. Gradual cyclosporine tappering from day +50 was initiated if mixed chimerism or persistent disease were present. We evaluated: engraftment rate, toxicities, transplant related mortality (TRM), chimerism kinetics, GVHD incidence and disease free and overall survival (DFS and OS).
Results: 18 lymphoma pts (8 follicular, 4 mantle cell, 4 peripheral T and 2 DLBCL) were transplanted since 5/2000 to 1/2007 due to co-morbidities in 4, age>55y in 6 and heavily pretreated pts in 10. Median age was 52y (31–61), 10 were males, median treatment lines were 3 (1–5) including 4 auto-transplanted(22%). After the last treatment, 10 pts were in CR(56%), 4 pts had chemo-sensitive PR(22%) and 4 chemo-resistant disease(22%). Median CD34+/kg infused cells were 5,0 x106(3,7–10,8) and 2,0 x108(0,4–4,4) CD3+ lymphocytes/kg. All pts engrafted, reaching ANC>500 on day +14 (10–20) and platelets>20.000 on day +12 (9–33), except 1 early death. There weren’t any early or late engrafment failures. Early toxicity until day +100 included febrile neutropenia in 6, severe mucositis in 2, hepatic toxicity in 2, VOD in 1, hemorragic cystitis and arrythmia in 1. There were 2 deaths before day +100: 1 refractory congestive heart failure and 1 Pseudomonas’ sepsis(TRM 11,1%) and 2 late deaths beyond +1y due to infections during chronic GVHD treatment. Viral infections were the most prevalent(72%), mainly CMV reactivations (44%) that were relapsing in 17%. There were 7 bacterial infections (4 bacteriemias, 1 meningitis, 1 pneumonia and 1 urinary sepsis). Complete chimerism (CC) was present on day +30 in 38% pts and in 93% pts on day +90. Only 1 pt persisted on mixed chimera until day +180 and 10/10 evaluated pts were on CC after 1 year. Acute grade II-IV GVHD ocurred in 37%, with 25% grade III-IV. Chronic GVHD affected 10/15 pts (67%), limited in 27% and extensive in 40%. Only 1/10 CR pts at transplant relapsed after 95 days and 4/4 pts with chemo-sensitive PR reached CR that persisted after achieving CC on day +90. All chemo-refractory pts died (4/4): 2 early toxic deaths and 2 progressions. Median follow-up was 55 months(28–83) with DFS of 61% and 66,7% OS at 5y. Twelve pts persisted alive in CR with chronic GVHD in 4(33%). Predictors for DFS and/or OS were follicular and mantle cell histology vs others (p<.01), CR or PR at transplant vs refractory (p<.01) and <3 pretreatment lines vs >2 lines (p<.06).
Conclusions: After long term follow-up, NMA conditioning with fludarabine and low melphalan dose in advanced lymphoma pts offers good toxicity profile, with high engraftment rate and good disease control if pts were in chemo-sensitive disease pretransplant.