A monocentric analysis of the long-term safety and efficacy of crizotinib in relapsed/refractory ALK+ lymphomas

Rindone, Giovanni; Bossi, Elisa; Verga, Luisa; Zambrotta, Giovanni Paolo Maria; Tarantino, Sara; Mussolin, Lara; Chiarle, Roberto; Gambacorti‐Passerini, Carlo

doi:10.1182/bloodadvances.2022007538

Cited by 9 publications

(10 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because the availability of patients in the MAPPYACTS trial was limited, we investigated samples from another series of patients with R/R ALK+ ALCL who had been treated with crizotinib and for whom clinical response was known and histology was available (NCT02419287 and EudraCT 2010-022978-14) ( 2 , 4 ). We previously demonstrated that crizotinib could induce long-lasting clinical responses in ALK+ ALCL ( 23 ), although some patients responded poorly and relapsed during crizotinib treatment ( 5 ).…”

Section: Resultsmentioning

confidence: 99%

“…Patients’ primary lymphoma samples obtained with informed consent under Dana-Farber/Harvard Cancer Center Institutional Review Board (IRB) protocol 14-076, and ALCL PDXs were used for scRNA-seq analysis. Patients’ primary samples for histological and immunohistochemical staining were enrolled in the phase 2 studies from 2010 to 2019 (NCT02419287 and EudraCT 2010-022978-14) ( 4 ).…”

Section: Methodsmentioning

confidence: 99%

“…Most anaplastic lymphoma kinase (ALK)-driven tumors respond well to treatment with ALK tyrosine kinase inhibitors (TKIs) (1). In ALK-rearranged anaplastic large cell lymphoma (ALCL), crizotinib, an ALK TKI, induces complete remissions that last for several years in most pediatric and adult patients with chemotherapy relapsed/refractory (R/R) disease (2)(3)(4). Because of this success, crizotinib received U.S. Food and Drug Administration approval in 2021.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma

et al. 2023

Self Cite

View full text Add to dashboard Cite

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. Although resistance mechanisms have been studied extensively in ALK-driven non–small cell lung cancer, they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…The effect was relatively rapid, as the median time to the first response was 3.9 weeks (28). Long term results confirmed the efficacy of the drug with relevant continuous complete remission rates and overall good tolerability (29). Interestingly, deletion of PTPN1 and PTPN2 phosphatases was related to the genesis of crizotinib resistance by upregulating SHP2 (30).…”

Section: Alk Signaling In Anaplastic Large Cell Lymphomamentioning

confidence: 85%

Tyrosine kinases in nodal peripheral T-cell lymphomas

Piccaluga

Cascianelli²,

Inghirami

2023

Front. Oncol.

View full text Add to dashboard Cite

Nodal peripheral T-cell lymphomas (PTCL) are uncommon and heterogeneous tumors characterized by a dismal prognosis. Targeted therapy has been proposed. However, reliable targets are mostly represented by a few surface antigens (e.g., CD52 and CD30), chemokine receptors (e.g., CCR4), and epigenetic gene expression regulation. In the last two decades, however, several studies have supported the idea that tyrosine kinase (TK) deregulation might be relevant for both the pathogenesis and treatment of PTCL. Indeed, they can be expressed or activated as a consequence of their involvement in genetic lesions, such as translocations, or by ligand overexpression. The most striking example is ALK in anaplastic large-cell lymphomas (ALCL). ALK activity is necessary to support cell proliferation and survival, and its inhibition leads to cell death. Notably, STAT3 was found to be the main downstream ALK effector. Other TKs are consistently expressed and active in PTCLs, such as PDGFRA, and members of the T-cell receptor signaling family, such as SYK. Notably, as in the case of ALK, STAT proteins have emerged as key downstream factors for most of the involved TK.

show abstract

“…In a retrospective study on 18 R/R ALK-positive patients treated with crizotinib monotherapy and followed with PCR for ALK fusion transcript on peripheral blood after 4 and 12 weeks, progression was observed in 1 of 10 patients with negative PCR, versus 5 of 7 patients with positive PCR at the 4th-week assessment, and in 0 of 9 patients with negative PCR versus 3 of 4 patients with positive PCR at the 12th-week assessment. In that study, only 1 patient underwent allogeneic HSCT, because the aim was to assess the safety and efficacy of crizotinib as a rescue treatment for relapsed/refractory ALCL, and not as a bridge to HSCT [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Refractory Anaplastic Large Cell Lymphoma Rescued by the Combination of the Second-Generation ALK Inhibitor Brigatinib, High-dose Chemotherapy and Allogeneic Stem Cell Transplantation: A Case Report and Review of the Literature

et al. 2023

Self Cite

View full text Add to dashboard Cite

The treatment of pediatric patients with refractory or relapsed anaplastic large cell lymphoma (ALCL) is still a major challenge. In addition to conventional chemotherapy and stem cell transplantation, new therapeutic options such as anti-CD30 drugs and anaplastic lymphoma kinase (ALK) inhibitors have been recently introduced in this setting. Among ALK inhibitors, only the first-generation molecule crizotinib is approved for pediatric use, while second-generation molecules, such as brigatinib, are still under investigation. Here we report the case of a 13-year-old boy diagnosed with stage IV ALCL, refractory to first-line conventional chemotherapy and second-line therapy with the anti CD30 antibody–drug conjugate brentuximab-vedotin, who finally achieved remission after a combination of conventional high-dose chemotherapy and the second-generation ALK inhibitor brigatinib. The latter was chosen for its ability to penetrate through the blood–brain barrier, due to the persistent involvement of the patient’s cerebral nervous system. The remission was then consolidated with an allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated donor using myeloablative conditioning with total body irradiation. At 24 months after HSCT, the patient is in complete remission, alive and well. An updated review regarding the use of ALK inhibitors in ALCL patients is provided.

show abstract

A monocentric analysis of the long-term safety and efficacy of crizotinib in relapsed/refractory ALK+ lymphomas

Cited by 9 publications

References 14 publications

Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma

Targeting CCR7-PI3Kγ overcomes resistance to tyrosine kinase inhibitors in ALK-rearranged lymphoma

Tyrosine kinases in nodal peripheral T-cell lymphomas

Refractory Anaplastic Large Cell Lymphoma Rescued by the Combination of the Second-Generation ALK Inhibitor Brigatinib, High-dose Chemotherapy and Allogeneic Stem Cell Transplantation: A Case Report and Review of the Literature

Contact Info

Product

Resources

About