PF509 MOLECULAR ANALYSIS OF PRIMARY CUTANEOUS DIFFUSE LARGE B‐CELL LYMPHOMA LEG TYPE AT DIAGNOSIS AND RELAPSE – IMPLICATIONS FOR TARGETED THERAPIES
Authors: Schrader A.M. R. , de Groen R.A. L. , Willemze R. , Jansen P.M. , Quint K.D. , Cleven A.H. G. , van Wezel T. , van Eijk R. , Ruano D. , Tensen C.P. , Hauben E. , Woei‐A‐Jin S. , Busschots A.M. , Vermeer M.H. , Vermaat J.S. P. 
Published: June 2019

Background:

Primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL‐LT) is an aggressive cutaneous lymphoma with a 5‐year disease‐specific survival (DSS) of ∼55%. In the past decades, survival hardly improved. Currently, no routine classifiers are available to predict patients at risk for relapsed/refractory disease and to adjust treatment strategies accordingly.

Aims:

To improve disease classification and risk stratification, we aimed to identify the clinical relevance of advanced molecular profiling in PCDLBCL‐LT.

Methods:

Using targeted NGS with a 52 B‐cell lymphoma‐related gene panel and stepwise ‘triple FISH’ (MYC/BCL2/BCL6), we investigated skin biopsies of 54 PCDLBCL‐LT patients, at diagnosis (n = 49) and at relapse (n = 20). Sequential analysis was available in 15 cases. Patients were diagnosed in the Leiden University Medical Center, the Netherlands, or the University Hospital Leuven, Belgium, between 2000 and 2019. The obtained profiles were correlated with the clinical characteristics and survival outcomes.

Results:

The cohort consisted of 54 patients, 27 (50%) females, with a median age at diagnosis of 78 (range 47–92) years. Median follow‐up duration was 81 (range 1–172) months. Additional clinical characteristics are presented in Figure 1. The 5‐year overall survival (OS) was 42% and the DSS 55%. At diagnosis (Figure 1A), highly frequent mutations were seen in MYD88 (69%) and CD79B (51%), both resulting in constitutive activation of the NF‐κB pathway. Other commonly mutated genes were PIM1 (29%), MYC (14%), BTG1 (12%), and TBL1XR1 (10%). MYC rearrangements were present in 26%, including one double hit (BCL6). At relapse (Figure 1B), common mutations were seen in MYD88 (75%), CD79B (55%), PIM1 (35%), MYC (15%), BTG1 (20%), and TBL1XR1 (20%), and MYC was rearranged in 39%. Sequential analysis showed newly obtained mutations in MYC and CD79B (n = 1), PIM1 (n = 2), and PRDM1 (n = 1), and rearrangements in MYC (n = 1) and a double hit in BCL6 (n = 1). In addition, circulating tumor DNA (ctDNA) was detected with digital droplet PCR in 3 of 4 patients harbouring MYD88
L265P, corresponding to the clinical disease status. Female gender and MYC rearrangements, especially in combination with a MYC mutation, showed an inferior OS (gender: p = 0.001, HR 3.88, 95% CI 1.61–9.36; MYC: p = 0.029, HR 1.80, 95% CI 1.06–3.06) and DSS (gender: p = 0.004, HR 6.96, 95% CI 1.97–24.61; MYC: p = 0.004, HR 2.76 95% CI 1.52–5.01) in univariate analysis (Figure 1C‐D). Multivariate analysis demonstrated independent prognostic significance of gender in OS (gender: p = 0.003, HR 4.16, 95% CI 1.63–10.61; MYC: p = 0.137) and both in DSS (gender: p = 0.006, HR 6.04, 95% CI 1.68–21.67; MYC: p = 0.008, HR 3.86, 95% CI 1.42–10.51).

Summary/Conclusion:

Our data corroborate the importance of the NF‐κB pathway as the major driver of lymphomagenesis in PCDLBCL‐LT, both at diagnosis (82%) and at relapse (90%). Secondly, MYC is commonly involved (26%) and associated with inferior survival. In addition, females had an independently adverse survival compared with males. The molecular profile of primary and relapsed disease largely overlaps without recurrently acquired alterations, suggesting that relapses may result from suboptimal initial therapy. The detection of ctDNA identifies liquid biopsy as a potentially new tool of monitoring treatment response and detecting minimally residual disease. Altogether, these results underline the need for precision medicine in PCDLBCL‐LT patients, with the NF‐κB pathway and MYC as the central targets for novel therapeutic approaches.

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