Pre-Transplant R-Bendamustine Induces High Rates of Minimial Residual Disease in MCL Patients: Updated Results of S1106: US Intergroup Study of a Randomized Phase II Trial of R-HCVAD Vs. R-Bendamustine Followed By Autologous Stem Cell Transplants for Patients with Mantle Cell Lymphoma
Authors: Chen Robert , Li Hongli , Bernstein Steven H. , Rimsza Lisa M. , Forman Stephen J. , Constine Louis , Shea Thomas C. , Cashen Amanda F. , Blum Kristie A. , Fenske Timothy S. , Barr Paul M. , Leblanc Michael , Fisher Richard I. , Cheson Bruce D. , Smith Sonali M. , Faham Malek , Wilkins Jennifer , Leonard John P. , Kahl Brad S. , Friedberg Jonathan W. 
Published: November 2019

Abstract
Introduction:
Aggressive induction chemotherapy followed by autologous stem cell transplant (ASCT) is effective for younger patients with mantle cell lymphoma (MCL). Among patients undergoing ASCT, cytarabine-based induction regimen induced higher rates of MRD-negativity compared to R-CHOP (Hermine et al, ASH 2012), and achievement of MRD-negative status was predictive of good outcome. R-bendamustine (RB) has superior efficacy compared to R-CHOP (Rummel et al, Lancet 2013; Flinn et al, Blood 2014) but, there are no data regarding its impact on MRD. S1106 (SWOG) was conducted to compare R-HyperCVAD/MTX/ARAC (RH) or RB to identify the better induction regimen followed by ASCT. We report the result of MRD analysis and updated 2 year PFS/OS.
Method:
S1106 was a US intergroup (SWOG/ECOG/CALGB), randomized phase II trial. The primary objective was to estimate 2 year PFS, with secondary objectives to assess response rates, OS, toxicities, and MRD status. Inclusion criteria were: untreated stage III, IV or bulky stage II MCL, Cyclin D1 +, age > 18 < 65, and adequate organ function. Randomization was stratified by MIPI. Patients received either 4 cycles of RH or 6 cycles of RB, followed by ASCT. MRD was assessed at baseline and post induction. Genomic tumor DNA was extracted from FFPE tissue or bone marrow aspirate mononuclear cells. PCR amplification of IGH-VDJ, IGH-DJ, and IGK regions was performed followed by high-throughput sequencing to determine the tumor clonotype(s) (Adaptive Biotechnologies). DNA from peripheral blood mononuclear cells (PBMC) and plasma was amplified and sequenced to determine lymphoma molecules per million diploid genomes.
Results:
A total of 53 patients were accrued out of planned 160. This study was closed prematurely based on predetermined criteria of stem cell mobilization failures on the RH arm. Table 1 shows patient characteristics. The ORR was 94% in RH vs. 83% in RB. The CR rates were 35% (RH) and 40% (RB). Only 4/17 patients on RH and 21/35 patients in RB underwent ASCT; the rest could not complete study (Table 1). RH induced significantly more grade 3/4 heme toxicities as compared to RB (Table 1). The median follow up was 29 months in RH and 26 months in RB. The estimated 2 year PFS was 81% (Fig 1) and OS was 87% for both arms.
27 patients consented to the optional MRD assessment, with 12 paired serial samples (baseline and post induction). 10 were in RB and 2 were in RH. Both patients in RH were MRD positive at baseline and achieved MRD negative status. 1/10 patient in RB was MRD negative at baseline and remained negative throughout treatment. 8/9 patients in RB with baseline MRD-positivity converted to MRD-negative status by the end of induction, and 3/8 did not go to ASCT. Three additional patients were missing baseline samples but were MRD negative at the end of RB. Overall, the estimated 2 year PFS was 100% for all 13 patients who achieved MRD negative status at the end of RB.
Conclusions:
RH is not an ideal platform for future transplant trials in MCL due to stem cell mobilization failures. RB achieved a 2 year PFS of 81%, higher than the planned target of 75%. It also achieved an 89% MRD negative rate on all the paired samples tested. Low CR on RB could be due to lack of mandatory PET. All patients with MRD negative status remain in remission, with some not having undergone ASCT. Premature closure of the study limited the sample size and the precision of PFS estimates and MRD. However, this analysis suggests that RB can achieve a deep remission and could be a platform for future trials in MCL.
Table 1. RH (n=17) RB (n=35) Age 59 (44-66) 57 (33-64) Male (p=0.003) Female 9 8 32 3 Performance status 0 1 11 6 26 9 Disease Stage III IV 1 16 3 32 B sx Yes No 6 11 10 25 BM involvement Positive Negative 14 3 31 4 Extranodal involvement Yes No 15 2 32 3 KI 67 <10% 10-30% >30% 20% 60% 20% 14% 66% 20% MIPI Score Intermediate/High Risk Low Risk 6 11 13 22 Grade 3/4 Hematological toxicities (Induction only) Anemia 56% Neutropenia 63% Febrile neutropenia 31% Thrombocytopenia 69% Anemia 8.6% Neutropenia 34% Febrile neutropenia 14% Thrombocytopenia 17% Reasons for early off treatment or not going to ASCT Failure to collect stem cell 5 Thrombocytopenia 4 Pancytopenia 1 Others 2 Patient choice 4 Progressive disease 2 Failure to collect stem cell 1 Allergy 1 Seizure 1 Insurance denial 1 Others 3
Figure 1. Figure 1.

Disclosures
Chen: genentech: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Millennium: Consultancy, Research Funding, Speakers Bureau. Forman:Mustang Therapeutics: Research Funding. Cashen:Celgene: Speakers Bureau. Blum:cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Fenske:Pharmacyclics: Honoraria; Millennium/Takeda: Research Funding; Seattle Genetics: Honoraria; Celgene: Honoraria. Cheson:Celgene: Consultancy, Research Funding; Spectrum: Consultancy; Astellas: Consultancy; Gilead: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; MedImmune: Research Funding; Ascenta: Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy; Teva: Research Funding. Smith:Pharmacyclics: Consultancy; Celgene: Consultancy. Faham:adaptive biotech: Employment, Other: stockholders. Wilkins:adaptive biotech: Employment. Leonard:teva: Consultancy; genentech: Consultancy. Kahl:Genentech: Consultancy; AbbVie: Research Funding; Teva: Consultancy.