Prospective Phase 2 Trial of High-Dose Gemcitabine/Busulfan/Melphalan (Gem/Bu/Mel) with Autologous Stem-Cell Transplant (ASCT) without Post-ASCT Maintenance, in Hodgkins Lymphoma Patients at High Risk of Post-Transplant Recurrence Comparison with a Concurrent Matched Cohort Treated with BEAM
Authors: Nieto Yago , Bassett Roland , Anderlini Paolo , Hosing Chitra M. , Alousi Amin M. , Popat Uday R. , Andersson Borje S. , Valdez Benigno C. , Shpall Elizabeth J. , Ahmed Sairah , Qazilbash Muzaffar , Guillermo Maria , Oki Yasuhiro , Fanale Michelle A. , Hagemeister Fredrick B. , Dabaja Bouthaina S. , Pinnix Chelsea C , Milgrom Sarah A , Tewari Priti , Champlin Richard E. , Jones Roy 
Published: October 2019

Abstract
INTRODUCTION:
More active high-dose regimens are needed for refractory or poor-risk relapsed Hodgkin's lymphomas (HL), where BEAM offers poor results. Post-BEAM maintenance treatment with brentuximab vedotin (BV) x 48 weeks has recently been shown in the AETHERA trial to prolong progression-free survival (PFS) compared to placebo (2-year PFS 63% vs. 51%). We previously developed a regimen of infusional gemcitabine combined with busulfan and melphalan (Gem/Bu/Mel) pursuing inhibition by Gem of DNA damage repair. The encouraging results we saw in HL patients led us to conduct a phase 2 trial of Gem/Bu/Mel in HL patients at high risk of post-ASCT relapse.
METHODS:
HL patients ages 12-65 with ≥1 of the following criteria were eligible: Persistent active disease after 1st-line chemotherapy, CR1 < 1 year, or extranodal disease at relapse/PD. Gem was administered as a loading dose of 75 mg/m2 followed by infusion at a fixed dose rate of 10 mg/m2/min over 4.5 hours on days -8 and -3 (total daily dose of 2,775 mg/m2). Each Gem infusion was immediately followed by the corresponding dose of Bu or Mel. Bu was administered intravenously from days-8 to -5 targeting a daily AUC of 4,000. Mel was infused at 60 mg/m2/day on days -3 and -2. ASCT was on day 0. Post-HDC involved field radiotherapy (IFRT) was considered to lesions >5 cm at the time of HDC or persistently PET+ at the 1-month post-HDC evaluation. The trial had 80% power to detect a 2-year PFS increase from 50% to 65%.The concurrent BEAM cohort included all patients eligible for this trial who received BEAM off study due to no financial coverage for ASCT in a trial or patient/physician preference.
RESULTS:
Eighty patients were enrolled on study between 6/11-04/15 (Table 1). There was no transplant-related mortality (TRM). The toxicity profile was manageable, including mucositis (49% G2, 40% G3), skin (22% G2, 11% G3), self-limited transaminase elevation (30% G2, 19% G3), and hyperbilirubinemia (24% G2, 19% G3) with no cases of VOD. There was 1 case of G2 pneumonitis and none of cardiac, renal or CNS toxicity. Neutrophils and platelets engrafted at median days +10 (8-12) and +12 (9-21), respectively. Eight patients received post-HDC IFRT to mediastinum ± neck ± sternum at 30.6-39.6 Gy, starting on median day +42 (41-53) post-HDC, which was well tolerated. No patients received maintenance BV.
Table 1. Patient characteristics Variable Study file (N=80) Concurrent BEAM cohort (N=31) P Median age (range) 31 (13-65) 39 (23-65) 0.02 Primary refractory / poor-risk relapse 41% / 59% 37% / 63% 0.6 # prior relapses 1 80% 70% 0.3 >1 20% 30% Median # prior chemotherapy lines (range) 2 (2-6) 2 (2-7) 0.3 Prior disease-free interval (months) <6 56% 60% 0.7 6-12 24% 17% >12 20% 23% Prior xRT 21% 27% 0.6 Relapse within prior xRT field 10% 3% 0.4 Extranodal relapse/PD 36% 53% 0.08 B symptoms at relapse/PD 11% 10% 0.8 Bulky relapse (any lesion >5 cm) 39% 17% 0.02 # risk factors (primary refract/CR1<1 yr, extranodal relapse, or B symptoms) 1 74% 77% 0.2 2 26% 17% 3 0% 6% Prior BV % 14% 25% 0.1 CR 36% 50% 0.1 PR 36% 0% No response (NR) 26% 50% PET+ at HDC 32% 7% 0.003 Status at HDC: CR/ PR / NR 68% / 24% / 8% 93% / 7% / 0% 0.01 At median follow-up of 33 mo (4-50) there have been 25 relapses following Gem/Bu/Mel, at median 6 (2-22) mo post-HDC (only 3 relapses after 12 mo). On univariate analyses, PET+ at HDC and primary refractoriness correlated with worse EFS (Table 2). On multivariate analyses, PET+ was an independent adverse predictor.
Table 2. Prognostic analyses Variable Univariate analyses Multivariate analyses 2-yr EFS P HR (95% CI) P Yes No PET+ 37% 82% 0.00008 3.8 (1.7-8.9) 0.001 Primary refractory 51.5% 81% 0.006 2.2 (0.9-5.1) 0.06 >1 relapse 50% 73% 0.08 B symptoms 55.6% 70.4% 0.2 Bulky relapse 67% 72% 0.2 Extranodal 67% 72% 0.4 The BEAM cohort included 31 patients treated between 06/11-04/15 (Table 1) with no BV maintenance. There were fewer cases of PET+ tumors at HDC (P=0.003) and of bulky relapses (P=0.02) than the Gem/Bu/Mel file, but was matched for the other risk factors. It had no TRM. Despite a higher number of PET+ tumors at HDC, the Gem/Bu/Mel file had significantly superior 2-year PFS (65% vs. 51%, P=0.03) and 2-year OS (95.5% vs. 70%, P=0.001) than the BEAM cohort.
CONCLUSIONS:
Gem/Bu/Mel without maintenance BV was safe and effective in patients with refractory or poor-risk relapsed HL, with comparable results to those from the AETHERA trial using BEAM and maintenance BV. A randomized trial is necessary to compare Gem/Bu/Mel and BEAM.
Figure 1. Figure 1.

Disclosures
Off Label Use: Gemcitabine, busulfan and melphalan are not FDA approved at high doses for Hodgkin's lymphoma. Alousi:Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding.