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

A B S T R A C T

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.

Keywords

Mantle cell lymphoma, TP53 mutation screening, survival, BCR inhibitors, BCL2 inhibitors, ASCT

Background

Mantle cell lymphoma (MCL) is a rare subtype of B-cell lymphoma, accounting for 5-9% of all cases [1]. The pathogenic hallmark in MCL is the t(11;14) (q13;q32) translocation, with resultant over-expression of cyclin D1 causing cell cycle disruption [1, 2]. Classical MCL is believed to arise from naïve B cells that express SOX11, and typically involves lymph nodes and extra-nodal sites such as the gastrointestinal tract. More aggressive forms of MCL with blastoid or pleomorphic morphologies could represent disease progression. The other type of MCL develops from antigen-experienced SOX11-negative B-cells. It mainly involves the peripheral blood, bone marrow, and spleen and is often clinically indolent, not requiring treatment. Although significant improvements have been made in treatments, patients with acquisition of secondary genetic abnormalities, in particular TP53 mutations have been associated with a very aggressive disease course [4]. Despite the prognostic impact of TP53 disruption in MCL, screening for this genetic aberration has not been incorporated in routine practice in this disease. In this review, we would like to highlight the important of TP53 disruption in MCL and propose incorporating this genetic defect screening in routine practice and we also suggest that patients with this defect should be treated with TP53-independent therapeutic approach in the era of novel therapies.

TP53 disruption & MCL

The median age at diagnosis is 65 years and the Mantle cell lymphoma International Prognostic Index (MIPI) is the most commonly used prognostic scoring system to predict which patients will have a more aggressive clinical course [6, 7]. TP53 mutation status was found to be the only independent molecular marker that was able to improve the prognostic value of the MIPI [8]. In recent years, next-generation sequencing has led to comprehensive mutational characterization of MCL [9]. TP53 mutations have recurrently demonstrated negative prognostic impact for the outcome of patients with MCL, and associated with inferior outcomes [9, 10]. MCL is associated with the highest degree of genomic instability of the B cell malignancies, and a large number of secondary chromosomal alterations have been described [11]. TP53 mutation, in particular, which is 15-20% more common in the blastoid variant, confers a dismal prognosis in MCL with a median survival of 1.3 years versus 5.1 years for non-mutated disease (p=0.023) [12, 13]. In contrast, the prognostic relevance of 17p deletion in MCL is less clear, although several studies have indicated an association with shortened survival [14, 15].

MCL current standard of care

Considerable improvement in progression-free survival (PFS) has been achieved with current first-line chemo-immunotherapy regimes affording approximately 2 years disease-free, and dose-intensified therapy with high-dose cytarabine and autologous stem cell transplant (ASCT) consolidation in eligible patients achieving up to 5 years PFS [16, 17]. Non-randomized studies suggest that this approach is as effective as and less toxic than more intensive chemotherapy (Hyper-CVAD).These intensive frontline therapies are a double-edged sword considering deaths due to toxicity and the rate of secondary malignancies (solid tumours 9.4%, Myelodyspalstic syndromes (MDS)/leukaemia 3.1–6.2% [18, 19]. Maintenance rituximab appears to prolong PFS and evidence suggests it may improve OS in patients treated with R-CHOP, but not those treated with Bendamustine-Rituximab (BR) [20]. More recently, the adoption of rituximab as maintenance therapy following an autograft has been shown to significantly improve progression-free survival (PFS) and overall survival (OS) [21]. Allogeneic bone marrow transplant is the only curative option for this disease and produces long-term disease-free remissions for a round 30-40% patients. However, many patients are ineligible for bone marrow transplant consolidation.

MCL patients usually respond well to initial treatment, however these responses are not durable, and relapse is inevitable. Individual heterogeneity in clinical behaviour is still encountered, ranging from primary refractory disease to a PFS of 7 years [22]. Excluding transplant eligible patients as the majority of relapsed MCL patients will not be eligible for ASCT or Allo-SCT, the median survival after first relapse of MCL is 1–2 years. There is no standard second line chemotherapeutic regimen at relapse and generally produce short lived response. In patients who have not received ASCT as a part of the first line therapy, a consideration of ASCT or Allo-SCT in younger patient is a clinical option in eligible patients. ASCT consolidation appears to be more beneficial to those achieving first CR after not more than two lines of therapy [17].

With the advent of the oral Bruton tyrosine kinase (BTK) inhibitor, Ibrutinib is highly active in the majority of relapsed MCL patients, and the duration of response provides a window to plan and perform the allograft procedure in young fit patient. Ibrutinib with or without anti CD20 monoclonal antibodies is the most promising therapeutic option in relapsed disease. Responses are seen in approximately two-thirds of patients with the majority lasting more than one year and relatively well tolerated. A phase II study of Ibrutinib involving patients with relapsed or refractory MCL showed a best overall response rate of 68%, a rate of complete response of 21%, and a median progression-free survival of 13.9 months. A phase III trial showed a best overall response rate of 72%, a rate of complete response of 19%, and a median progression-free survival of 14.6 months [23, 24]. Different therapeutic options are available in relapsed disease, however, the choice of therapy will be influenced by age, performance status, co morbidities and initial therapy.

Target therapy in MCL

MCL is associated with the highest degree of genomic instability in the B-cell malignancy, and a large number of secondary chromosomal alterations have been described [11]. TP53 mutation confers a dismal prognosis with inferior outcomes in MCL with a median survival of 1.3 years versus 5.1 years for non-mutated disease (p=0.023) [12]. Despite a significant improvement in disease outcomes achieved by the addition of Rituximab and high-dose Cytarabine to chemotherapy regimes, and consolidation with ASCT, which is considered to be the current standard of care for younger patients, this approach does not directly target TP53 mutated MCL patients [18, 25].

Ibrutinib, Bruton’s tyrosine kinase (BTK) inhibitor and Venetoclax, BCL2 inhibitor (ABT-199) are two of the most active agents in the treatment of chronic lymphocytic leukaemia (CLL) and MCL with an acceptable toxicity profil [26, 27]. In the phase III trial, Ibrutinib was superior to tem¬sirolimus with regard to response rates, safety profile, and progression-free survival [26]. Common or serious side effects of Ibrutinib include bleed¬ing due to platelet dysfunction diarrhoea, rash, and atrial fibrillation [24, 26, 28]. Resistance to Ibrutinib in mantle-cell lymphoma is often related to acti¬vating mutations in the nuclear factor κB (NF-κB) pathway whereas in resistant chronic lympho¬cytic leukaemia, mutations of BTK and PLCγ2 pathways are implicated [29-31].

Venetoclax is a BH3-mimetic agent that di¬rectly and specifically inhibits BCL2 induc¬ing apoptosis in malignant cells when BCL2 is over expressed [32, 33]. In a phase 1 study, Venetoclax had greatest single-agent activity, among B-cell can¬cers, against chronic lymphocytic leukaemia and mantle-cell lymphoma both of which highly express BCL2 [27]. Across a range of doses in patients with relapsed or refractory MCL, a best overall response rate of 75% and a complete response rate of 21% were reported, with a median progression-free survival of 14 months [27]. Pre-clinical models predict synergy in these novel drugs in combination (Ibrutinib and Venetoclax) or Ibrutinib and Bortezomib) [24, 34]. This could possibly overcome drug refractoriness. Emerging evidences yielded perhaps less impressive results when Ibrutinib was used later in the disease course, of which partially related prior therapy inducing selective advantage of resistant clone expansion. Most recent phase II trial reported by Constantine et al 2018, suggest dual targeting of BTK and BCL2 with Ibrutinib and Venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy with low toxicity profile [35]. Such an approach might challenge the current standard of care including the role of ASCT consolidation in this disease.

Mangament of TP53 disruptet MCL

The available different therapeutic approaches in MCL, do not consider the high heterogeneity in the evolution of the disease in MCL patients. Although MIPI score has shown the capacity to clearly separate MCL patients into three groups with significantly different prognoses, it has no therapeutic decision impact on this disease [7]. Optimal management of MCL patient’s harbouring TP53 mutation is un-met clinical need, and alternative therapeutic approaches independent of the TP53 pathway should be considered. In addition, unselected and ineffective therapy, a part of therapy related toxicities, this approach could also induce a resistant disease clone. These observations could partially explain the less impressive response to Ibrutinib mono-therapy when used in second line settings. The activity of targeted therapy in the relapse setting has prompted the development of front-line therapy trials in combination with chemo-immunotherapy [36, 37].

In contrast, screening for 17p deletion by FISH and TP53 mutational status is now included in the routine assessment of chronic lymphocytic leukaemia (CLL) and more importantly, treatment algorithm are divided into two main groups depending on the presence or absence of TP53 disruption [38]. The same has been observed in MCL, including disease heterogeneity, incidence and impact of TP53 disruption on disease course and treatment outcome12. This is not altogether surprising, as conventional chemo-immunotherapy relies on an intact TP53 pathway, it seems logical that the management of MCL patients might benefit from a similar approach. We believe MCL patients with mutant TP53 status might be best treated upfront with specific therapy independent of the TP53 pathway using, BCR inhibition, BCL2 Inhibitors or in combinations, +/- Allogeneic stem cell transplantation (if eligible) in the upfront setting. The use of Ibrutinib as a single agent in relapsed patients has yielded perhaps less impressive results than expected. Selection of treatment-resistant clones by the use of standard first-line therapies in patients with aberrant TP53 has been hypothesized as a possible explanation for this [19]. This concern could be avoided by using Ibrutinib in combinations, with, for example BCL2 inhibitors (Venetoclax) as this combination has been proven to be effective in relapse setting [35]. In contrast, MCL patients without TP53 mutation should be treated with chemo-immunotherapy and ASCT consolidation or rituximab maintenance as appropriate.

Conclusion

MCL continues to be challenging disease therapeutically despite recent significant developments. Our ability to further refine and integrate TP53 mutation screening into our prognostic workup will improve our treatment algorithm allowing a more personalized approach to treat this disease with improved efficacy and minimal toxicity. We believe that MCL patients harbouring TP53 mutations should be considered for alternative upfront therapies, and non-mutated cases should receive the current standard of care with chemo-immunotherapy and ASCT where suitable. A larger clinical trial urgently needed for this un-met clinical need to optimise up-front treatment approach in this sub-set of patients.

Article Info

Article Type
Research Article
Publication history
Received: Mon 02, Sep 2019
Accepted: Wed 18, Sep 2019
Published: Wed 09, Oct 2019
Copyright
© 2021 Ezzat Elhassadi. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
DOI: 10.31487/j.ACO.2019.03.05

Author Info

Corresponding Author
Ezzat Elhassadi
Consultant Haematologist, Honorary Clinical Lecturer for UCC & RCSI, Clinical Director for Haematology and transfusion services, University Hospital Waterford, Ireland

Figures & Tables

References

  1. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK et al. (1994) A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 84: 1361-1392. [Crossref]
  2. Swerdlow SH, Campo E, Harris NL (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press.
  3. (1997) A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’sLymphoma Classification Project. Blood 89: 3909-3918. [Crossref]
  4. Martin P, Chadburn A, Christos P, Weil K, Furman RR et al. (2009) Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol 27: 1209-1213. [Crossref]
  5. Vose JM (2012) Mantle cell lymphoma: 2012 update on diagnosis, risk-stratification, and clinical management. Am J Hematol 87: 604-609. [Crossref]
  6. Møller MB, Pedersen NT, Christensen BE (2006) Mantle cell lymphoma: prognostic capacity of the Follicular Lymphoma International Prognostic Index. Br J Haematol 133: 43-49. [Crossref]
  7. Hoster E, Dreyling M, Klapper W, Gisselbrecht C, van Hoof A et al. (2008) A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood 111: 558-565. [Crossref]
  8. Slotta-Huspenina J, Koch I, de Leval L, Keller G, Klier M et al. (2012) The impact of cyclin D1 mRNA isoforms, morphology and p53 in mantle cell lymphoma: p53 alterations and blastoid morphology are strong predictors of a high proliferation index. Haematologica 97: 1422-1430. [Crossref]
  9. Kridel R, Meissner B, Rogic S, Boyle M, Telenius A et al. (2012) Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood 119: 1963-1971. [Crossref]
  10. Halldórsdóttir AM, Lundin A, Murray F, Mansouri L, Knuutila S et al. (2011) B Sander and R Rosenquist Impact of TP53 mutation and 17p deletion in mantle cell lymphoma. Leukemia 25: 1904-1908. [Crossref]
  11. Jares P, Colomer D, Campo E (2012) Molecular pathogenesis of mantle cell lymphoma. J Clin Invest 122: 3416-3423. [Crossref]
  12. Greiner TC, Moynihan MJ, Chan WC, Lytle DM, Pedersen A et al. (1996) p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. Blood 87: 4302-4310. [Crossref]
  13. Dreyling MH, Bullinger L, Ott G, Stilgenbauer S, Müller-Hermelink HK et al. (1997) Alterations of the cyclin D1/p16-pRB pathway in mantle cell lymphoma. Cancer Res 57: 4608-4614. [Crossref]
  14. Allen JE, Hough RE, Goepel JR, Bottomley S, Wilson GA et al. (2002) Identification of novel regions of amplification and deletion within mantle cell lymphoma DNA by comparative genomic hybridization. Br J Haematol 116: 291-298. [Crossref]
  15. Rubio-Moscardo F, Climent J, Siebert R, Piris MA, Martin-Subero JI et al. (2005) Mantle-cell lymphoma genotypes identified with CGH to BAC microarrays define a leukemic subgroup of disease and predict patient outcome.  Blood 105: 4445-4454. [Crossref]
  16. Herrmann A, Hoster E, Zwingers T, Brittinger G, Engelhard M et al. (2009) Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol 27: 511-518. [Crossref]
  17. Dreyling M, Geisler C, Hermine O, Kluin-Nelemans HC, Le Gouill S et al. (2014) Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25: iii83-iii92. [Crossref]
  18. Eskelund CW, Dahl C, Hansen JW, Westman M, Kolstad A et al. (2017) TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood 130: 1903-1910. [Crossref]
  19. Cheah CY, Chihara D, Romaguera JE, Fowler NH, Seymour JF et al. (2015) Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes.  Ann Oncol 26: 1175-1179. [Crossref]
  20. Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M et al. (2012) Treatment of older patients with mantle-cell lymphoma. N Engl J Med 367: 520-531. [Crossref]
  21. Augustin A, Le Gouill S, Gressin R, Bertaut A, Monnereau A et al. (2018) Survival benefit of mantle cell lymphoma patients enrolled in clinical trials; a joint study from the LYSA group and French cancer registries. J Cancer Res Clin Oncol 144: 629-635. [Crossref]
  22. Delarue R, Haioun C, Ribrag V, Brice P, Delmer A et al. (2013) CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d’Etude des Lymphomes de l’Adulte. Blood 121: 48-53. [Crossref]
  23. Wang ML, Rule S, Martin P, Goy A, Auer R et al. (2013) Targeting BTK with Ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369: 507-516. [Crossref]
  24. Rule S, Dreyling M, Goy A, Hess G, Auer R et al. (2017) Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies. Br J Haematol 179: 430-438. [Crossref]
  25. Delfau-Larue MH, Klapper W, Berger F (2015) CDKN2A and TP53 deletions predict adverse outcome in younger mantle cell lymphoma patients, independent of treatment and MIPI. Blood 126: 604-611.
  26. Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C et al. (2016) Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet 387: 770-778. [Crossref]
  27. Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS et al. (2017) Phase I First-in-Human Study of Venetoclax in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma. J Clin Oncol 35: 826-833. [Crossref]
  28. Bojarczuk K, Sasi BK, Gobessi S, Innocenti I, Laurenti L et al. (2015) Inhibition of SYK More Effectively Overcomes MCL-1 Mediated ABT-199 Resistance of BCR-Stimulated CLL Cells Than Inhibition of BTK or PI3Kdelta. Blood 126: 489.
  29. Wu C, de Miranda NF, Chen L, Wasik AM, Mansouri L et al. (2016) Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations. Oncotarget 7: 38180-38190. [Crossref]
  30. Balasubramanian S, Schaffer M, Deraedt W, Davis C, Stepanchick E et al. (2014) Mutational Analysis of Patients with Primary Resistance to Single-Agent Ibrutinib in Relapsed or Refractory Mantle Cell Lymphoma. Blood 124: 78.
  31. Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M et al. (2014) Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib. N Engl J Med 370: 2286-2294. [Crossref]
  32. Roberts AW, Huang D (2017) Targeting BCL2 With BH3 Mimetics: Basic Science and Clinical Application of Venetoclax in Chronic lymphocytic Leukemia and Related B Cell Malignancies. Clin Pharmacol Ther 101: 89-98. [Crossref]
  33. Jares P, Colomer D, Campo E (2007) Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. Nat Rev Cancer 7: 750-762. [Crossref]
  34. Portell CA, Axelrod M, Brett LK, Gordon VL, Capldo B et al. (2014) Synergistic cytotoxicity of Ibrutinib and the BCL2 antagonist, ABT-199(GDC-0199), inmantle cell lymphoma (MCL) and chronic lymphocytic leukaemia (CLL): molecular analysis reveals mechanisms of target interactions. Blood 124: 509.
  35. Tam CS, Anderson MA, Pott C, Agarwal R, Handunnetti S et al. (2018) Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. N Engl J Med 378: 1211-1223. [Crossref]
  36. Robak T, Huang H, Jin J, Zhu J, Liu T et al. (2015) Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med 372: 944-953. [Crossref]
  37. Albertsson-Lindblad A, Kolstad A, Laurell A (2015) Lenalidomide-rituximab-bendamustine in first line for patients > 65 with mantle cell lymphoma: final results of the Nordic Lymphoma Group MCL4 (LENA-BERIT) phase I/II trial. Hematol Oncol 33: 100-180.
  38. Zenz T, Vollmer D, Trbusek M, Smardova J, Benner A et al. (2010) TP53 mutation profile in chronic lymphocytic leukemia: evidence for a disease specific profile from a comprehensive analysis of 268 mutations.  Leukemia 24: 2072-2079. [Crossref]