TRAF1-ALK Fusion Predicts Poor Prognosis for ALK Positive Anaplastic Large Cell Lymphoma Patients with Chemotherapy and ALK Inhibitor

Background: Relapsed/refractory anaplastic lymphoma kinase (ALK) positive anaplastic large cell lymphomas (ALCLs) respond to ALK inhibitors, but resistance, which bear a poor prognosis. No biomarkers were found to predict long duration of response to ALK inhibitors. The ALK gene was first identified as the fusion partner of the nucleophosmin (NPM1) gene in the recurrent t(2;5)(p23;q35) found in a subset of ALCL. However, several distinct ALK fusions which result in highly different characteristics have also been described in lymphomas. Methods: We retrospectively reviewed seven relapsed/refractory ALK positive ALCLs who received ALK inhibitors (six with Crizotinib and one with Alectinib) at Guangdong Provincial People's Hospital from June 2007 through March 2019. We did next generation sequencing (NGS) with paraffin-embedded tissue for two patients who quickly developed resistance. Results: Of the seven patients, four were male and three were female, with a median age of 18 years (range 15-51) old. The median line of therapies was four (range 3-7) and that of ALK inhibitor usage was three (range 2-5). The overall response rate was 7 of 7 (100%) and the median overall survival of 21.2 months (8.5-86 months). Three patients obtained complete response (CR) on Crizotinib and then received autologous stem cell transplantation, and are still CR. One patient obtained CR, but died of serious infection five months after allogeneic stem cell transplantation. One patient is in CR under continuous crizotinib administration. One patient received Crizotinib obtained CR, but three months later got progression disease, the NGS showed TNF receptor-associated factor 1 gene (TRAF1) exon 6-ALK exon 20 fusion junction. The last patient was CR on alectinib, but quickly developed resistance, with a progression free survival of 1 month, the NGS indicated TRAF1 exon 7-ALK exon 20 fusion. Conclusions: ALK inhibitors improved survival of relapsed/refractory ALK positive ALCLs. TRAF1-ALK fusion may predict poor clinical outcome to chemotherapy and ALK inhibitors. This ALK fusion may reflect a trend to aggressive behaviour in lymphomas. Disclosures Li: Guangdong Province Hospital: Employment.

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TRAF1-ALK fusion indicates poor prognosis to ALK tyrosine kinase inhibitors in relapsed/refractory ALK-positive anaplastic large-cell lymphoma patients

10.21203/rs.3.rs-39803/v1 ◽

2020 ◽

Author(s):

Diwen Pang ◽

Ling Huang ◽

Xinmiao Jiang ◽

Feili Chen ◽

Hanguo Guo ◽

...

Keyword(s):

Anaplastic Large Cell Lymphoma ◽

Poor Prognosis ◽

Cell Lymphoma ◽

Bone Marrow Involvement ◽

Large Cell ◽

Fusion Partner ◽

Alk Inhibitors ◽

Anaplastic Lymphoma ◽

Large Cell Lymphoma ◽

Alk Positive

Abstract Background Relapsed/refractory (R/R) anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) respond to ALK inhibitors, but resistance bears a poor prognosis. No biomarkers predict a long duration of response to ALK inhibitors. The ALK gene was first identified as the fusion partner of the nucleophosmin (NPM1) gene in recurrent t(2;5)(p23;q35) found in an ALCL subset. However, several distinct ALK fusions that result in highly different characteristics have also been described in lymphomas. Methods We retrospectively reviewed 43 patients with pathologically confirmed ALK-positive ALCL at Guangdong Provincial People’s Hospital from February 2007 through February 2020, including seven R/R patients who received ALK inhibitors (six with crizotinib and one with alectinib). We performed next-generation sequencing (NGS) with paraffin-embedded tissue for these seven R/R patients and one patient with a peripheral blood sample. We evaluated clinical characteristics and survival status. Results The median age of all patients was 29 (range 15–66) years. Most patients were male with advanced stage and B symptoms. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 60% and 70%, respectively with a median follow-up of 52.2 (range 2.4–168.6) months. Multivariate analyses revealed that only bone marrow involvement was an independent prognostic factor for PFS (P = 0.03) and OS (P = 0.03). Of the seven R/R patients, the median line number of therapies was four (range 3–7) and that of ALK inhibitor usage was three (range 2–5). The overall response rate was 100% (n = 7). The NGS identified four patients with the NPM1-ALK fusion and two with tumor necrosis factor receptor-associated factor 1 gene (TRAF1)-ALK fusion; the latter quickly developed resistance to chemotherapy and ALK inhibitors. Conclusions ALK inhibitors improved survival of patients with R/R ALK-positive ALCLs. TRAF1-ALK fusion may predict a poor clinical outcome to chemotherapy and ALK inhibitors. This ALK fusion may reflect a trend toward the aggressive behavior of lymphomas.

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