Is TP53 mutation screening in Mantle Cell Lymphoma (MCL) ready for prime time?

Abstract

Mantle cell lymphoma (MCL) is a rare incurable subtype of B-cell lymphoma characterized by t(11;14)(q13;q32)-driven over expression of cyclin D1 [1]. MCL is associated with the highest degree of genomic instability of the B cell malignancies, and TP53 mutation in particular confers a dismal prognosis in MCL with a reported incidence of 15-20 % (blastoid=29% vs Classical= 6%) [2, 3]. TP53 mutation status is the only independent molecular marker that was able to improve the prognostic value of the Mantle cell lymphoma International Prognostic Index (MIPI) [4]. MCL Patients with a TP53 mutation were significantly less likely to achieve a CR after first-line treatment and associated early relapse. The current standard of care, Chemo-immunotherapy with high-dose Cytarabine followed by autologous stem cell transplant (ASCT) (in eligible patient), although most patients prove ineligible, have failed to overcome the poor prognostic impact of TP53 disruption [4]. Ibrutinib and Venetoclax (ABT-199) are two of the most active agents in the treatment of MCL, they have acceptable toxicity profiles and mainly are used in relapse setting. Pre-clinical models predict synergy between these novel drugs in combination. Patients who received Ibrutinib after an initial relapse had significantly longer PFS and OS than patients who received Ibrutinib after successive relapses probably related to selective advantage of resistant clone expansion [5]. In MCL, the attention should be move to the upfront treatment setting using these target therapies in high risk disease (TP53 mutated) and elderly patients whom un-fit for chemo-immunotherapy approach and phase III clinical trial eagerly awaited to support this approach. Likewise, in chronic lymphocytic leukaemia (CLL) incorporating TP53 mutation screening in routine practice prior commencing therapy is paramount in the era of novel effective therapies. Younger MCL patients with this genetic alteration should be considered for specific treatment using inhibitors for BCR, BCL2, TP53-independent pathways, the Anti-CD20 monoclonal antibodies either alone or in combination followed by allogeneic stem cell transplantation in the upfront setting. Chemo-free approach also to be considered for un-fit patients early in the disease course. Fit un-mutated TP53 MCL Patients should be treated with chemo-immunotherapy with ASCT consolidation if eligible and anti CD20 monoclonal antibody maintenance therapy.