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1691 Distinct Subtypes of Chemotherapy-Resistant Systemic ALK-Positive Anaplastic Large Cell Lymphoma Demonstrate Long-Term Complete Remissions to Imatinib

Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphomas and T/NK Cell Lymphomas: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphomas, Non-Biological therapies, Clinical Research, genomics, T Cell lymphoma, Diseases, Therapies, Lymphoid Malignancies, Pharmacology, Biological Processes
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Alexander Pichler1*, Christoph Kornauth, MD2*, Ines Garces De Los Fayos Alonso, MSc3*, Lukas Kazianka4*, Arne Zibat5*, Luca Mologni, PhD6*, Halima Alachram5*, Tea Pemovska7*, Gerwin Heller, PhD4*, Richard Greil, MD8, Lukas Kenner4*, Ulrich Jaeger, MD1* and Philipp Bernhard Staber, MD, PhD1

1Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria
2MLL Munich Leukemia Laboratory, Munich, Germany
3University of Veterinary Medicine Vienna, Vienna, AE, AUT
4Medical University of Vienna, Vienna, AUT
5Institute of Human Genetics, Georg August University of Goettingen, Goettingen, Germany
6Department of Medicine and Surgery, University Milano-Bicocca, Monza, Italy
7Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria
8Paracelsus Medical University, Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Salzburg, Austria

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.

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).

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.

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.

Disclosures: 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.

OffLabel Disclosure: Imatinib as platelet-derived growth factor receptor (PDGFR)and kinase inhibitor in ALK+ Anaplastic Large Cell lymphoma

*signifies non-member of ASH