Population Based Observational Study Demonstrates Significant Increase in Watch-and-Wait for Newly Diagnosed Mantle Cell Lymphoma
Authors: McCulloch Rory , Berrow Margie , Wainman Brian , Crosbie Nicola , Pettitt Andrew , Rule Simon 
Published: October 2019

Abstract
Background: Mantle cell lymphoma (MCL) is associated with a poor prognosis relative to other indolent B-cell lymphomas where clinicians have traditionally been reluctant to adopt watch-and-wait (W+W) strategies. US registry data from 2004 to 2011 demonstrated 6% of new diagnoses were observed beyond 3 months from diagnosis (Cancer 2016; 122: 2356-63), although other studies have demonstrated higher rates of W+W with no detriment to patient survival.
Currently no consensus exists on how to determine suitability for W+W. The MCL Biobank Observational Study was set up to capture clinical behaviour across the United Kingdom and to characterise patients enrolled to W+W compared to those who receive upfront systemic therapy. The study remains open to recruitment.
Method: From January 2015 to April 2017 222 patients from 49 centres in the United Kingdom enrolled to the study. All new MCL diagnoses compatible with WHO diagnostic criteria were eligible, with no specific exclusion criteria. Baseline data was recorded at entry including investigator decision to start systemic therapy or enter W+W. Clinical updates were provided at 6 month intervals.
In contrast to previous studies W+W was defined as a period lasting at least 1 year from date of diagnosis.
Results: All patients were followed-up for a minimum of 1 year. The median age was 70 (range 32-90), 69.4% were male and 47.1% were MIPI high risk.
At 1 year follow-up 60 patients (27.0%) were on W+W, 141 (63.5%) received systemic therapy, 16 (7.2%) received isolated radiotherapy and 5 (2.3%) received palliative care. At 2 year follow-up 16 of 85 patients (18.9%) remained on W+W. There were no deaths recorded in patients on W+W. Estimated 2-year survival of the whole population was 80.6%.
Univariate analysis comparing baseline characteristics of patients on W+W with those receiving systemic therapy showed no significant difference in age (median age 71.7 vs 69.0; p=0.48), baseline WCC (median 8.0 x 109/L vs 8.9 x 109/L; p=0.09) or performance status (ECOG >1 OR 0.7; p=0.51) meaning the MIPI was not predictive of suitability for W+W (MIPI high risk OR 1.18; p=0.61). Positive predictors for W+W included measures of low disease proliferation: LDH ratio <1.0 (p=<0.001), Beta-2-microglobulin < 3.5 mcg/ml (p=0.011) and Ki67 <30% (p=0.001). In addition, female sex (p=0.010) predicted for indolent behaviour. Measures of high disease burden were generally negative predictors including presence of B symptoms (p=0.001), haemoglobin <100 g/L (p=0.014) and stage IV disease (p=<0.001). The absence of measurable disease on CT was predictive of W+W (p=0.009), although measurable disease was identified in the majority of cases (70.2%) illustrating most patients on W+W were not the leukaemic, non-nodal subtype.
Conclusion: This study demonstrates that adoption of W+W in the United Kingdom significantly exceeds use in previous observational studies and highlights a fundamental shift in clinical approach. The results show that conservative management can be reasonably adopted in a significant proportion of patients. Patients with low disease burden appear best candidates and markers of cell turnover may aid clinical judgement. The MIPI does not have a role in this setting. Longer follow-up will establish if W+W confers survival benefit.

Disclosures
Pettitt: Celgene: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Gilead: Research Funding; Napp: Research Funding; GSK/Novartis: Research Funding; Chugai: Research Funding. Rule:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees.