Gemcitabine (Gem) /Clofarabine (Clo) /Busulfan (Bu) (GemCloBu): A New Myeloablative Conditioning Regimen with Reduced Toxicity and High Activity for Allogeneic Stem-Cell Transplant (alloSCT) for Aggressive Lymphomas

AlloSCT is used for patients (pts) with relapsed lymphomas pursuing a graft-vs-lymphoma effect. Reduced intensity conditioning regimens increased its safety but their insufficient cytotoxicity can cause aggressive lymphomas to progress rapidly after alloSCT. Seeking more active conditioning regimen we studied 2 nucleoside analogues (Gem + Clo) followed by Bu, which showed synergy in lymphoma cell lines through DNA damage repair inhibition (Valdez, Leuk Lymphoma 2012). Those preclinical observations led us to clinically study GemCloBu for alloSCT in pts with aggressive lymphomas. Methods Eligibility included age 12-65; refractory aggressive B-NHL (de novo / transformed LBCL / Burkitt), T-NHL and Hodgkin (HL); adequate end-organ function, and 8/8 HLA-matched sibling (MSD) or unrelated donor (MUD). Gem was escalated days (d) -6 and -4 as loading dose of 75 mg/m2 followed by infusion at 10 mg/m2/min over 40-90 min (total daily dose 475 (dose level (DL)1), 675 (DL2) or 975 mg/m2 (DL3), followed by Clo (40 mg/m2/day x 4) on d-6 to -3, and Bu (pharmacokinetically targeting a daily AUC of 4,000 μMol•min x 4, d-6 to -3). AlloSCT was on d0. Pts with CD20+ tumors received rituximab (375 mg/m2, d-14, -7, +1 and +8). GVHD prophylaxis included ATG (in MUD)), tacrolimus and MMF. Results We enrolled 64 pts, median age 46 (17-63), 31 B-NHL, 22 T-NHL, 11 HL, after a median 4 (2-10) prior therapy lines; 18 pts (28%) after failure of prior auto-SCT; 42 pts (66%) with active disease at alloSCT (PD in 12); 36 and 28 pts received a MSD and MUD alloSCT, respectively. The MTD of gemcitabine was DL3 (975 mg/m2/day x 2) Regimen-related toxicities were manageable, including mucositis (47% G2, 42% G3), self-limited transaminitis and hyperbilirubinemia.The regimen was myeloablative, with neutrophils decreasing to <0.1 in all pts on median d0 (-2 to +2) and engrafting on median d+10 (+9 to +20). The rates of grade II-IV and III-IV acute GVHD were 37% (33% MSD, 42% MUD) and 18% (25% MSD, 8% MUD), respectively. Chronic GVHD in 33% pts (12% mild, 8% moderate, 13% severe). 39 pts died: 20 from tumor relapse, 13 from infection (3 with concurrent acute GVHD and 3 with chronic GVHD), 4 from chronic GVHD, and 2 from second primary lung cancer.The γ-H2AX levels drawn at baseline, day -5 and d-3 increased in PBMNC (N=19) after treatment, to a median 8.5 fold from baseline (range, 0.4-46.3) (P=0.0001) and PARP-1 decreased by a median 0.45 fold (0.2-6.3) (P=0.4), indicative of activation of DNA damage response and apoptosis, respectively.The ORR/CR rates in 42 evaluable pts were: B-NHL: 78.5%/71%, T-NHL: 93%/93%, and HL: 67%/67%. The d100/1-year NRM rates were 7.8%/18.75%. At median follow-up of 60 months (12-110) the EFS/OSrates are 36%/47%. The EFS/OS rates in B-NHL were both 54%, and in T-NHL were 62%/69%. Conclusion GemCloBu is a new myeloablative conditioning regimen with reduced toxicity and high activity for allo-SCT for refractory aggressive lymphomas.