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

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 1^st-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.