Minimal Residual Disease (MRD) Status Following Induction Chemo-Immunotherapy Predicts Progression-Free Survival In Mantle Cell Lymphoma (MCL): CALGB 50403 (Alliance)
Authors: Fulton Noreen , Johnson Jeffrey , Kaplan Lawrence D. , Koval Greg , Malnassy Greg , Jung Sin-Ho , Devine Steve , Shea Thomas C. , Leonard John P. , Cheson Bruce D. , Stock Wendy 
Published: October 2019

Abstract
CALGB 50403 was a randomized phase II clinical trial to test the benefit of maintenance vs consolidation bortezomib therapy following aggressive chemo-immunotherapy and autologous stem cell transplant for adults < 60 years old with previously untreated mantle cell lymphoma (MCL). Eradication of minimal residual disease has been found to be an important biomarker of Progression Free Survival (PFS) in MCL. One goal of this study was to assess the kinetics of MRD during treatment of 50403: intensive chemo-immunotherapy induction; autologous stem cell mobilization and transplant; and post transplant therapy with rituximab followed by intensive bortezomib consolidation or prolonged bortezomib maintenance therapy.

Methods
151 patients were enrolled in this study. 93 patients had adequate follow-up samples available and were screened for IgH/BCL-1 gene rearrangements using standardized primer sets (InVivoscribe). The sensitivity of this assay is from 1X104-105. 61/93 (66%) had an evaluable MRD marker and sequential samples for study of MRD kinetics. Patient specific oligonucleotides were generated from pre-treatment bone marrow for quantitative PCR (qPCR) amplification using previously published, standardized methods. The sensitivity of detection of MRD ranges from 1X104-105. 49 patients with sequential bone marrow samples at a minimum of 3 timepoints during and following treatment are included in this analysis. Presenting characteristics: the median age was 59 years (29-69); 32 (65%) were male; Stage IV MCL in 46 (94%); 16 (33%) had B-symptoms, 46 (94%) had PS 0 or 1; 17 (35%) had elevated LDH; MIPI risk group: Low 25 (51%), Intermediate 13 (26%) and high 11 (23%) ; 24 (49%) were randomized to maintenance bortezomib; 19 (39%) to bortezomib consolidation, and six were not randomized (12%).

Results
With a median f/u of 3.3 years from study registration, there have been 12 events amongst these 49 Patients: 10 with disease progression and 2 deaths from other causes (censored at time of death). PFS is defined as time from study entry until progression, or date of last follow-up. Early eradication of MRD following 2 cycles of intensive induction chemo-immunotherapy was significantly and independently associated with PFS (p =0.017), (Figure 1). None of the patients who achieved MRD negative status (n=15) following chemo-immunotherapy induction have progressed. Conversely, 10/32 patients with any level of MRD positivity at this time-point have suffered disease progression. No other clinical variables described above were associated with PFS or MRD status. MRD status prior to bortezomib randomization is also significantly associated with PFS, but to a lesser degree (p=0.05) while MRD measurements in the apheresis product did not predict for PFS.

Conclusions
Early achievement of undetectable MRD using qPCR for IgH gene rearrangements is highly prognostic for PFS for patients with MCL treated on CALGB 50403, with an observed 100% PFS amongst these patients. Longer follow-up is required to determine whether one of the two bortezomib arms improves treatment outcome compared to earlier CALGB studies in MCL. Nevertheless, these data suggest that the early introduction of novel agents into the 50403 treatment regimen may be a useful strategy for improving MRD eradication and PFS in MCL.

Disclosures:
Cheson: MedImmune: Research Funding.