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1980 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

Clinical Autologous Transplantation: Results
Program: Oral and Poster Abstracts
Session: 731. Clinical Autologous Transplantation: Results: Poster I
Saturday, December 5, 2015, 5:30 PM-7:30 PM
Hall A, Level 2 (Orange County Convention Center)

Yago Nieto, M.D., Ph.D.1, Roland Bassett, MS2*, Paolo Anderlini, MD1, Chitra M. Hosing, MD1, Amin M. Alousi, MD1, Uday R. Popat, MD1, Borje S. Andersson, MD, PhD1, Benigno C. Valdez, PhD1, Elizabeth J. Shpall, MD1, Sairah Ahmed, MD1, Muzaffar Qazilbash, M.D.1, Maria Guillermo3*, Yasuhiro Oki, MD4, Michelle A. Fanale4, Fredrick B. Hagemeister, MD5, Bouthaina S. Dabaja, MD6, Chelsea C Pinnix, MD PhD6*, Sarah A Milgrom, MD6*, Priti Tewari, MD7, Richard E. Champlin, MD1 and Roy Jones, MD, PhD1*

1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
2Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
3Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
6Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
7Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX

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. 

ASH 2015

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.

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 .

*signifies non-member of ASH