Radioimmunotherapy-Based Conditioning with Yttrium-90 Ibritumomab Tiuxetan Plus High Dose BEAM for Non-Hodgkin Lymphoma: Does the Regimen Matter?

Background: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) has played an important role in the treatment of relapsed or refractory non-Hodgkin lymphoma (NHL). Several studies demonstrate that standard-dose ⁹⁰Y ibritumomab tiuxean (0.4 mci/kg) (Zevalin) plus high-dose BEAM (BCNU, etoposide, cytarabine, and melphalan) (ZBEAM) is a well-tolerated HCT preparative regimen. Herein we report the outcomes of a prospective single-arm phase II study of ZBEAM conditioning in three CD20+ NHL histologic strata: mantle cell (MCL), diffuse large B cell (DLBCL), and follicular (FL)/transformed (TF). The study was designed to detect a 20% improvement in PFS, within each stratum, over historical rates for BEAM alone at 2-years post HCT with ~80% power, α=0.05.

Patients and Methods: Patients with histologically confirmed CD20⁺ MCL, DLBCL, FL, or TF were eligible if they failed induction therapy, had relapsed disease or poor risk disease (Table 1). Patients with DLBCL or FL were classified as poor risk if they failed to achieve a complete response after induction chemotherapy or had high-/high-intermediate-risk features per the age-adjusted International Prognostic Index (IPI) at diagnosis. All MCL and TF lymphomas were considered poor risk, including those in first remission.

Results: The median follow-up for surviving patients: 43 months (range: 3-79). The estimated PFS and overall survival (OS) probabilities at 3 years were between 47-75% and 82-91%, respectively (Table 2); non-relapse mortality (NRM) was <1% overall. Adverse events ≥ grade 3 within the first 100-days included grade 3 infection (n=8) per CTCAE 3.0, grade 3 GI toxicity (n=1) per Bearman Toxicity Scale and grade 4 infection (n=1) per CTCAE 3.0.

Conclusion: Across histologies, high OS and low NRM confirm the safety and tolerability of the regimen, while improvements in 2-year PFS compared to historical controls in DLBCL and MCL are notable^1-4 leading us to conclude that, in the case of MCL and DLBCL, RIT based conditioning improves outcome compared to high dose chemotherapy alone. The strikingly high PFS within the DLBCL subgroup, even though this strata had the highest percentage of induction failure patients serve as a basis for an ongoing multinational randomized phase III trial comparing ZBEAM to BEAM for the treatment of relapsed/ IF DLBCL.

Table 1. Patient and Disease Characteristics (#/% or median/range)

Variable	All N = 116	MCL N = 32	DLBCL N = 46	FL N = 20	TF N = 18
Disease status at HCT    1st complete remission    1st partial remission    1st relapse    2nd complete remission    ≥3rd complete remission    Induction failure	29 (25) 7 (6) 20 (17) 20 (17) 3 (3) 37 (32)	23 (72) 4 (13) 0 (0) 1 (3) 0 (0) 4 (13)	4 (9) 1 (2) 8 (17) 12 (26) 0 (0) 21 (46)	0 (0) 1 (5) 6 (30) 4 (20) 1 (5) 8 (40)	2 (11) 1 (6) 6 (33) 3 (17) 2 (11) 4 (22)
Prior regimens	2 (1–7)	1 (1–3)	2 (2–7)	3 (1–4)	2 (1–3)
Age at transplant, yr	57 (23–75)	60 (43–72)	48 (23–75)	57 (43–67)	58 (41–65)
Maintenance rituximab    No    Yes    N/Aa	103 (89) 12 (10) 1 (1)	23 (72) 9 (28) 0 (0)	44 (96) 2 (4) 0 (0)	20 (100) 0 (0) 0 (0)	16 (89) 1 (6) 1 (6)

Abbreviations: MCL, mantle cell lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; TF, transformed lymphoma; HCT, hematopoietic cell transplantation; N/A, not available. a) The follow-up time for 1 patient had not reached Day +30 post-HCT at the time the analytical data were locked.

Table 2. Outcomes, % (95% CI)

	Allb N = 115	MCL N = 32	DLBCL N = 46	FL/TF, combinedb N = 20/17, 37
BEAM, historical estimates:    2-yr PFS	N/A	35	45	45/35, 40
ZBEAM, trial estimates:    2-yr PFS	70 (61-78)	78 (57-89)	78 (62-87)	54 (30-73)/57 (31-77), 56 (38-70)
3-yr PFS	66 (56-74)	69 (54-79)	75 (63-83)	47 (36-58)/57 (42-70), 52 (35-67)
3-yr OS	85 (77-91)	91 (72-98)	83 (70-90)	85 (65-94)/82 (60-92), 83 (67-92)

Abbreviations: PFS, progression-free survival; OS, overall survival. b) At the time of abstract submission, the follow-up time for 1 of the 116 patients was not sufficient for outcomes to be reported (<100 days post-HCT).

References 1) Mills W, et al. J Clin Oncol 1995;13:588-595. 2) Shimoni A, et al. Cancer 2012;118:4706-4714. 3) Kolstad A et al. Blood 2014;123:2953-2959. 4) Berger MD et al. Hematol Oncol 2015; doi:10.1002/hon

Disclosures: Krishnan: celgene: Consultancy , Equity Ownership , Speakers Bureau ; millennium: Speakers Bureau ; onyx: Speakers Bureau ; jannsen: Consultancy ; jazz: Consultancy ; spectrum: Consultancy . Off Label Use: Zevalin combined with BEAM. Nademanee: Gilead: Consultancy ; Celgene: Consultancy ; Seattle Genetics Inc.: Research Funding ; Spectrum: Research Funding . Chen: Genentech: Consultancy , Speakers Bureau ; Seattle Genetics, Inc.: Consultancy , Other: Travel expenses , Research Funding , Speakers Bureau ; Millennium: Consultancy , Research Funding , Speakers Bureau . Forman: Mustang: Research Funding ; Amgen: Consultancy .

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