Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition

Masood, Ashiq; Christ, Trevor N; Asif, Samia; Rajakumar, Priya; Gustafson, Beth A; Shune, Leyla; Salahudeen, Ameen A.; Nedvad, Drew; Nanua, Suparna; Paner, Agne; Kuzel, Timothy M.; Levy, Mia A.; Subramanian, Janakiraman; Raza, Shahzad

doi:10.1038/s41525-021-00186-9

Cited by 6 publications

(9 citation statements)

References 19 publications

(20 reference statements)

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“…This driver effect is important to consider as it indicates that inhibition of this central fusion gene and associated pathways could potentially reduce tumor growth. Importantly, studies have shown that ALK translocated tumors are highly sensitive to targeted ALK inhibitor therapies ( 10 , 16 , 29 ). Presently, crizotinib is the most well studied ALK inhibitor in ALK+ LBCL and it induces a transient improvement in lymphadenopathy and serum LDH levels, though this has been followed by rapid progression and a survival time of less than 6 months ( 5 ).…”

Section: Discussionmentioning

confidence: 99%

TFG::ALK fusion in ALK positive large B-cell lymphoma: a case report and review of literature

et al. 2023

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Anaplastic lymphoma kinase (ALK) positive large B-cell lymphoma (ALK+ LBCL) is an aggressive and rare subtype of B-cell lymphoma. Patients typically present with advanced clinical stage disease and do not respond to conventional chemotherapy; the median overall survival is 1.8 years. The genetic landscape of this entity remains poorly understood. Here we report a unique case of ALK+ LBCL harbouring a rare TFG::ALK fusion. Targeted next-generation sequencing showed no significant single nucleotide variants, insertions/deletions, or other structural variants beyond the TFG::ALK fusion; deep deletions of FOXO1, PRKCA, and the MYB locus were also detected. Our case report draws attention to this rare disease, highlights a need for larger genetic profiling studies, and focuses on the pathogenesis and potential therapeutic targets of this aggressive disease. To our knowledge, this is the first report of a TFG::ALK fusion in ALK+ LBCL.

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Section: Discussionmentioning

confidence: 99%

TFG::ALK fusion in ALK positive large B-cell lymphoma: a case report and review of literature

et al. 2023

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“…KIF5B is the most common ALK fusion partner. Others observed DCTN1, TPM3, EML4 and TFG fusions with ALK 74 Leukemia RANBP2-ALK fusion has been reported in an AML case 63 ALK mutations in 2/185 (<1%) cases of leukemias) 63 , 90 Multiple myeloma TFG-ALK fusion has been reported in non-secretory multiple myeloma TFG-ALK fusion has been reported in non-secretory multiple myeloma 73 Abbreviations: ALCL anaplastic large cell lymphoma, ALL acute lymphoblastic leukemia, AML acute myelogenous leukemia, EML4 echinoderm microtubule-associated protein like-4, GBM glioblastoma multiforme, IHC immunohistochemistry, IMT inflammatory myofibroblastic tumor, KIF5B kinesin family member 5B, NPM1 nucleophosmin1, NSCLC non-small cell lung cancer, PPP1CB protein phosphatase 1 catalytic subunit beta, RANBP2 RAN binding protein 2, TFG TRK-fused gene, TPM3 tropomyosin 3. a ALK alterations in AACR genie database included rearrangements, mutations and amplification.…”

Section: Alk Alterations In Solid and Hematologic Malignanciesmentioning

confidence: 99%

“…ALK inhibitors have shown activity in a range of solid tumors and hematologic malignances and have achieved approval in the rare solid tumor IMT and in the hematologic malignancy ALCL, in addition to the NSCLC approval (Table 1 ) 28 – 34 , 36 – 39 and (Table 4) 35 , 48 , 73 , 74 , 85 , 94 , 126 , 130 – 149 .…”

Section: Alk-targeted Therapiesmentioning

confidence: 99%

“…(NCT00939770) NPM-ALK fusion Phase I/II Crizotinib 12/14 (86%) Circulating tumor-derived NPM-ALK transcript decreased with response. 130 IMT ( N = 2) Usually bear ALK fusions Case series Brigatinib 1/2 (50%) 134 IMT of head and neck ( N = 1 SQSTM1-ALK fusion gene Case report Alectinib 1/1 (100%) DOR 17+ months 135 Mesothelioma (peritoneal) STRN-ALK Fusion Case report Ceritinib 1/1(100%) DOR 3+mths 144 Multiple myeloma, non-secretory ( N = 1) Myeloma TFG-ALK fusion Case report Alectinib 1/1(100%) DOR 24+months 73 Neuroblastoma ( N = 1) ALK mutation at exon 24 F1245C Case report Alectinib 1/1 (100 %) DOR 12+ months 136 Neuroblastoma ( N = 28) A New Approaches to Neuroblastoma Consortium study ALK mutations/amplifications Phase I Lorlatinib In (2–17) age group, 1/18 (5%) In (15–50) age group, 4/10 (40%) 148 Ovarian Cancer (Refractory high-grade serous) [ N = 1] EML4-ALK Fusion Case report Alectinib 1/1(100%) 147 Pancreatic adenocarcinoma ( N = 1) PPFIBP1-ALK fusion Case report Alectinib/ Lorlatinib Minor response with alectinib lasted for 5 months.Pt. achieved stable disease for 2 months on lorlatinb 94 Pancreatic adenocarcinoma ( N = 1) …”

Section: Alk-targeted Therapiesmentioning

confidence: 99%

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ALK fusions in the pan-cancer setting: another tumor-agnostic target?

Shreenivas,

Janku,

Gouda

et al. 2023

npj Precis. Onc.

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Anaplastic lymphoma kinase (ALK) alterations (activating mutations, amplifications, and fusions/rearrangements) occur in ~3.3% of cancers. ALK fusions/rearrangements are discerned in >50% of inflammatory myofibroblastic tumors (IMTs) and anaplastic large cell lymphomas (ALCLs), but only in ~0.2% of other cancers outside of non-small cell lung cancer (NSCLC), a rate that may be below the viability threshold of even large-scale treatment trials. Five ALK inhibitors –alectinib, brigatinib, ceritinb, crizotinib, and lorlatinib—are FDA approved for ALK-aberrant NSCLCs, and crizotinib is also approved for ALK-aberrant IMTs and ALCL, including in children. Herein, we review the pharmacologic tractability of ALK alterations, focusing beyond NSCLC. Importantly, the hallmark of approved indications is the presence of ALK fusions/rearrangements, and response rates of ~50–85%. Moreover, there are numerous reports of ALK inhibitor activity in multiple solid and hematologic tumors (e.g., histiocytosis, leiomyosarcoma, lymphoma, myeloma, and colorectal, neuroendocrine, ovarian, pancreatic, renal, and thyroid cancer) bearing ALK fusions/rearrangements. Many reports used crizotinib or alectinib, but each of the approved ALK inhibitors have shown activity. ALK inhibitor activity is also seen in neuroblastoma, which bear ALK mutations (rather than fusions/rearrangements), but response rates are lower (~10–20%). Current data suggests that ALK inhibitors have tissue-agnostic activity in neoplasms bearing ALK fusions/rearrangements.

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“…1 There are various ALK gene fusion partners, including predominant partner echinoderm microtubule-associated protein-like 4 (EML4) 2 and other rare non-EML4 partners, such as HIP1, 3 KLC1, 4 KIF5B, 5 TPR, 6 and TFG. 7 More than 15 EML4-ALK variants have been identified based on the occurrence of EML4 internal breakpoints at different sites; of these, variant 1 (v1; exon 13 of EML4 fused to exon 20 of ALK [E13;A20]), and variant 3a/b (exon 6a/b of EML4 fused to exon 20 of ALK [E6a/b;A20]) are the most frequent. 2 Since the approval of first-generation ALK inhibitor, crizotinib, multiple second-(e.g., ensartinib, alectinib, and brigatinib) and third-generation (e.g., lorlatinib) ALK-TKIs have been approved for the treatment of patients with ALKrearranged NSCLC, all with higher potency or greater central nervous system penetration than crizotinib.…”

Section: Introductionmentioning

confidence: 99%

Association of anaplastic lymphoma kinase variants and alterations with ensartinib response duration in non‐small cell lung cancer

et al. 2021

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Background: Here, we aimed to assess the association of ALK variants and alterations with ensartinib response duration in NSCLC, and explore the potential value of computed tomography (CT) radiomic features in predicting progression-free survival (PFS). Methods: We enrolled 88 patients with identified ALK variant NSCLC in a multicenter phase 2 trial, and assessed the impact of ALK variants and secondary ALK alterations on the clinical outcome (response duration) of patients receiving ensartinib. We also established a multifactorial model of clinicopathological and quantitative CT radiomic features to predict PFS and risk stratification. Kaplan-Meier analysis was conducted to identify risk factors for tumor progression. Results: Univariate analysis indicated a statistical difference (p = 0.035) in PFS among ALK variants in three classifications (V1, V3, and other variants). Secondary ALK alterations were adversely associated with PFS both in univariate (p = 0.008) and multivariate (p = 0.04) analyses and could identify patients at high risk for early progression in the Kaplan-Meier analysis (p = 0.002). Additionally, response duration to crizotinib <1 year and liver metastasis were adversely associated with PFS. The combined model, composed of clinicopathological signature and CT radiomic signature, showed good prediction ability with the area under the receiver operating characteristic curve being 0.85, and 0.89 in the training and validation dataset respectively. Conclusions: Our study showed that secondary ALK alterations were adversely associated with ensartinib efficacy, and that ALK variants might not correlate with PFS.

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Non-secretory multiple myeloma with unusual TFG-ALK fusion showed dramatic response to ALK inhibition

Cited by 6 publications

References 19 publications

TFG::ALK fusion in ALK positive large B-cell lymphoma: a case report and review of literature

TFG::ALK fusion in ALK positive large B-cell lymphoma: a case report and review of literature

ALK fusions in the pan-cancer setting: another tumor-agnostic target?

Association of anaplastic lymphoma kinase variants and alterations with ensartinib response duration in non‐small cell lung cancer

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