Distinct Subtypes of Chemotherapy-Resistant Systemic ALK-Positive Anaplastic Large Cell Lymphoma Demonstrate Long-Term Complete Remissions to Imatinib

• Published in: Blood Vol. 142; no. Supplement 1; p. 1691
• Main Authors: Pichler, Alexander, Kornauth, Christoph, Garces De Los Fayos Alonso, Ines, Kazianka, Lukas, Zibat, Arne, Mologni, Luca, Alachram, Halima, Pemovska, Tea, Heller, Gerwin, Greil, Richard, Kenner, Lukas, Jaeger, Ulrich, Staber, Philipp Bernhard
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 02-11-2023
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-188835

Background
Platelet-derived growth factor receptor (PDGFR) is expressed in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) positive anaplastic large cell lymphomas (ALCL ALK+). Our previous preclinical research suggested that PDGFR blockade by the Abl/c-Kit/PDGFR kinase inhibitor imatinib could be an effective treatment strategy for ALCL ALK+. An indicator patient whose ALCL cells expressed PDGFR and who failed three treatment lines (including autologous stem cell transplantation) achieved complete remission (CR) with imatinib.
Methods
We treated 6 relapsed/refractory (r/r) ALK+ ALCL patients with imatinib, 4 of which within the prospective clinical trial, EudraCT No.: 2013-003505-26. Median follow-up was 40 months (160 weeks, range 4 - 428). Patients were characterized by whole exome sequencing, bisulfite sequencing, RNA-sequencing and immunological profiling. Whole exome sequencing data were integrated and compared to 32 additional ALK+ ALCL patients (Larose et. al., Haematologica, 2021; Creszenzo et al., Cancer Cell 2015; Mologni et al. (unpublished).
Results
5-year progression-free survival (PFS) was 67%. 4 out of 6 patients achieved a CR that was maintained throughout the follow-up of 3.3 - 8.9 years. Lymphoma cells of the non-responding patients did not express PDGFRA/B as confirmed by immunohistochemistry and RNA-scope (panel figure A). Cytoplasmic co-expression of both, ALK and PDGFRA/B, in ALCL tumor cells was associated with complete response to imatinib in ALK+ ALCL patients. Methylation profiling confirmed a differentially activated PDGFR axis between responders and non-responders and identified a specific protein kinase profile that included a significant inflammatory upregulation of HGFAC, VEGFa, and TNFa in serum cytokine profiling. The transcriptional differential gene expression includes an upregulation of genes of GO:0045859 (regulation of protein kinase activity) in non-resonders. Ident pathologic variants resulting in amino-acid changes were detected in non-responders in mutated genes linked to kinase activity ( TBC1D28 E56A), protein processing ( EMC1 S323T: cosmicV64345386 and EMC1S325N: cosmicV100916421; and GOLGA8S) and cytokine signaling ( IFNL2, ZFYVE19). The imatinib-resitance profile involving mutations in EMC1 and GOLGA8S could be detected at a frequency of 6/32 (19%) in an independent reference cohort of r/r ALK+ALCL (panel figure B). Exclusive mutations in PPP1R13B linked to p53-pathway were found in all responders. PDGFRA mutations with low allele frequencies (2-5%) were identified soley in imatinib-responders. Additionally, non-responders were characterized by an exclusive mutational signature linked to vesicular endocytosis and cytokine signaling as a resistance mechanism to pan-kinase inhibitor imatinib.
Conclusion
PDGFRA/B expression in tumour cells of therapy-resistant ALK-positive ALCL patients can discriminate genetically and functionally distinct lymphoma subgroups that are directly related to long-term treatment response to kinase inhibitor imatinib. Our data suggests that significant imatinib responses may be achieved in more than 80% of chemotherapy-resistant ALK+ ALCL cases.
Pichler:Takeda: Honoraria. Kornauth:MLL Munich Leukemia Laboratory: Current Employment. Greil:Roche: Honoraria, Research Funding. Jaeger:BMS, Novartis, Gilead, Miltenyi, Janssen and Roche: Honoraria; Innovative Medicines Initiative 2 Joint Undertaking: Research Funding.
Imatinib as platelet-derived growth factor receptor (PDGFR)and kinase inhibitor in ALK+ Anaplastic Large Cell lymphoma
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