The ALK inhibitor ASP3026 eradicates NPM-ALK+ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma characterized by expression of the oncogenic NPM/ALK fusion protein. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis is very poor. In these patients, the ALK inhibitor crizotinib achieves high response rates, however 30–40% of them develop further resistance to crizotinib monotherapy, indicating that new therapeutic approaches are needed in this population. We here investigated the efficacy of upfront rational drug combinations to prevent the rise of resistant ALCL, in vitro and in vivo. Different combinations of crizotinib with CHOP chemotherapy, decitabine and trametinib, or with second-generation ALK inhibitors, were investigated. We found that in most cases combined treatments completely suppressed the emergence of resistant cells and were more effective than single drugs in the long-term control of lymphoma cells expansion, by inducing deeper inhibition of oncogenic signaling and higher rates of apoptosis. Combinations showed strong synergism in different ALK-dependent cell lines and better tumor growth inhibition in mice. We propose that drug combinations that include an ALK inhibitor should be considered for first-line treatments in ALK+ ALCL.

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51 Small cell/lymphohistiocytic morphology is associated with CD8 positivity, retained T cell markers, a trend of decreased PD-L1 expression, but not outcome in adults with ALK+ ALCL

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0051 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A54-A54

Author(s):

Mahsa Khanlari ◽

Shaoying Li ◽

Roberto N Miranda ◽

Swaminathan Iyer ◽

Cameron Yin ◽

...

Keyword(s):

T Cell ◽

Anaplastic Large Cell Lymphoma ◽

Cell Lymphoma ◽

Large Cell ◽

Small Cell ◽

Adult Patients ◽

World Health ◽

Proliferation Index ◽

Cell Markers ◽

Large Cell Lymphoma

BackgroundSeveral morphologic patterns of ALK+ anaplastic large cell lymphoma (ALCL) are recognized: common, small cell, lymphohistiocytic, Hodgkin-like, and composite patterns.1 Small cell (SC) and lymphohistiocytic (LH) patterns are thought to be closely associated with poorer outcome in children with ALK+ ALCL.2 However, the clinicopathologic and prognostic features of SC/LH patterns of ALK+ ALCL are not yet reported in adults. Recently, we found PD-L1 expression in a large subset of ALK+ ALCL cases, however, PD-L1 expression in SC/LH versus non-SC/LH ALCL has not been reported.MethodsAmong 102 adult patients with ALK+ ALCL seen at our institution from January 1, 2007 through August 30, 2018, 18 (18%) cases had a SC and/or LH pattern. The clinical, pathologic, and outcome data were compared between SC/LH and non-SC/LH ALK+ ALCL cases using Fisher’s exact test. Overall survival (OS) was analyzed using the Kaplan-Meier method and compared using the log-rank test.ResultsThere were no significant differences in clinical features including age, gender, nodal versus extranodal involvement, B symptoms, stage, leukocytosis/lymphocytosis, and serum LDH levels between patients with SC/LH versus non-SC/LH ALK+ ALCL. Compared to non-SC/LH cases, SC/LH ALCL was more often positive for CD2 (92% vs. 36%, p = 0.0007), CD3 (81% vs. 15%, p = 0.0001), CD7 (80% vs. 37%, p = 0.03), and CD8 (54% vs. 7%, p = 0.0006). SC/LH ALCL showed a trend of decreased PD-L1 expression than non-SC/LH cases (24% vs. 46%, p = 0.11). There were no significant differences in the expression of CD4, CD5, CD25, CD43, CD45, CD56, TCR A/B, TCR G/D, cytotoxic markers, EMA, Ki-67 proliferation index. The induction chemotherapy and response rate in patients with SC/LH ALK+ ALCL were similar to patients with non-SC/LH ALK+ ALCL. After a median follow-up of 30.5 months (range, 0.3–224 months), there was no significant difference in OS between patients with SC/LH versus non-SC/LH ALK+ ALCL (p = 0.88).ConclusionsIn adults with ALK+ALCL, the SC/LH morphologic pattern is associated with a CD8+ T cell immunophenotype and retention of expression of T cell markers (CD2, CD3, and CD7). The trend of decreased PD-L1 expression in SC/LH ALCL suggests that these patients may not be ideal candidates for PD-L1 immunotherapy. The SC/LH patterns of ALK+ ALCL have no impact on the prognosis of adult patients which is in contrast to the reported association of the SC/LH patterns with poorer outcome in children with ALK+ ALCL.Ethics ApprovalThe study was approved by the Institutional Review Board at MD Anderson Cancer Center, Approval number: PA16-0897ReferencesSwerdlow SH, Campo E, The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375–2390.Brugières L, Deley MC, CD30 (+) anaplastic large-cell lymphoma in children: Analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood 1998;92:3591–3598.

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Primary Cutaneous CD30-Positive Anaplastic Large Cell Lymphoma in Childhood: Report of 4 Cases and Review of the Literature

Pediatric and Developmental Pathology ◽

10.1007/s10024-004-8087-6 ◽

2005 ◽

Vol 8 (1) ◽

pp. 52-60 ◽

Cited By ~ 39

Author(s):

Shimareet Kumar ◽

Stefania Pittaluga ◽

Mark Raffeld ◽

Michael Guerrera ◽

Nita L. Seibel ◽

...

Keyword(s):

T Cell ◽

Anaplastic Large Cell Lymphoma ◽

Cell Lymphoma ◽

Subcutaneous Tissue ◽

Pediatric Population ◽

Large Cell ◽

Lymphoid Cells ◽

Cell Phenotype ◽

Anaplastic Lymphoma ◽

Large Cell Lymphoma

We present the clinicopathologic findings in 4 children with primary cutaneous anaplastic large cell lymphoma (C-ALCL). The patients ranged in age from 13 months to 8 years, with 3 females and 1 male. All presented with a rapidly enlarging mass involving the skin and subcutaneous tissue. Histologic evaluation showed sheets of large pleomorphic lymphoid cells that were diffusely and strongly CD30+. Tumor cells were CD45+ in 1 of 4 cases. Cells were of T-cell phenotype, with variable positivity for CD3 (3 of 4 cases) and CD5 (2 of 4 cases). All 4 cases were positive for CD4 and clusterin. Staining for anaplastic lymphoma kinase was negative in all cases. No evidence of systemic involvement was noted at initial presentation or over a follow-up of 5 to 78 months, although 3 patients had cutaneous recurrences. Primary C-ALCL has only rarely been described in the pediatric population. The high-grade histologic appearance of this lymphoma belies its generally favorable clinical course and prognosis. Recognition of this entity and its differentiation from other T-cell lymphomas that secondarily involve the skin is important to avoid unnecessarily aggressive therapy in these children.

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Malignant hematopoietic cell lines: in vitro models for the study of anaplastic large-cell lymphoma

Leukemia ◽

10.1038/sj.leu.2403465 ◽

2004 ◽

Vol 18 (10) ◽

pp. 1569-1571 ◽

Cited By ~ 10

Author(s):

H G Drexler ◽

R A F MacLeod

Keyword(s):

Cell Lines ◽

Anaplastic Large Cell Lymphoma ◽

Cell Lymphoma ◽

Large Cell ◽

In Vitro Models ◽

Hematopoietic Cell ◽

Large Cell Lymphoma ◽

Hematopoietic Cell Lines

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Anaplastic Large Cell Lymphoma Arising in Bone

Archives of Pathology & Laboratory Medicine ◽

10.5858/2000-124-1339-alclai ◽

2000 ◽

Vol 124 (9) ◽

pp. 1339-1343

Author(s):

Mark A. Lones ◽

Warren Sanger ◽

Sherrie L. Perkins ◽

L. Jeffrey Medeiros

Keyword(s):

T Cell ◽

Anaplastic Large Cell Lymphoma ◽

Cell Lymphoma ◽

Correct Diagnosis ◽

Cell Lineage ◽

Antigen Expression ◽

Large Cell ◽

Null Cell ◽

Anaplastic Lymphoma ◽

Large Cell Lymphoma

Abstract Anaplastic large cell lymphoma (ALCL) represents approximately 2% of all non-Hodgkin lymphomas according to the recent Non-Hodgkin Lymphoma Classification Project. As defined in the revised European-American classification of lymphoid neoplasms (REAL), ALCL is a neoplasm of T-cell or null-cell lineage; 20% to 60% of cases are associated with the t(2;5)(p23;q35) translocation. ALCL commonly involves nodal as well as a wide variety of extranodal sites, although primary or secondary involvement of bone is rare. We describe the case of a 71-year-old man with stage IE T-cell ALCL, monomorphic variant, arising in the left anterior fifth rib and involving adjacent soft tissue without other sites of disease. The monomorphic histologic features hindered the initial recognition of this neoplasm as ALCL. However, strong uniform CD30 antigen expression and subsequent demonstration of the t(2;5)(p23;q35) translocation and anaplastic lymphoma kinase (ALK) immunoreactivity led to the correct diagnosis. We identified only 5 reported cases of T-cell and null-cell ALCL arising in bone and only 2 of these cases involved a single bone site. All 5 previously reported cases were ALCL of the classic type. We report a case of ALCL that is unique to our knowledge. This case of monomorphic ALCL was localized to bone and tumor cells contained the t(2;5)(p23;q35) translocation.

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The Role of IgM Antibodies in T Cell Lymphoma Protection in a Novel Model Resembling Anaplastic Large Cell Lymphoma

The Journal of Immunology ◽

10.4049/jimmunol.2001279 ◽

2021 ◽

pp. ji2001279

Author(s):

Chuancang Jiang ◽

Ming-Lang Zhao ◽

Luis Ramos ◽

Katarzyna Dobaczewska ◽

Ronald Herbert ◽

...

Keyword(s):

T Cell ◽

Anaplastic Large Cell Lymphoma ◽

Cell Lymphoma ◽

Large Cell ◽

T Cell Lymphoma ◽

Igm Antibodies ◽

Large Cell Lymphoma ◽

Novel Model

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How I treat breast implant–associated anaplastic large cell lymphoma

Blood ◽

10.1182/blood-2018-03-785972 ◽

2018 ◽

Vol 132 (18) ◽

pp. 1889-1898 ◽

Cited By ~ 25

Author(s):

Neha Mehta-Shah ◽

Mark W. Clemens ◽

Steven M. Horwitz

Keyword(s):

T Cell ◽

Anaplastic Large Cell Lymphoma ◽

Cell Lymphoma ◽

Breast Implant ◽

Large Cell ◽

World Health ◽

Team Approach ◽

Textured Surface ◽

Complete Surgical Excision ◽

Large Cell Lymphoma

Abstract Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is a recently described form of T-cell non-Hodgkin lymphoma now formally recognized by the World Health Organization classification of lymphoid neoplasms. The disease most often presents with a delayed seroma around the breast implant, almost exclusively with a textured surface, and manifests with breast pain, swelling or asymmetry, capsular contracture, but can also present with a breast mass, and lymph node involvement. The prognosis of BIA-ALCL is favorable compared with many other subtypes of systemic T-cell lymphoma; however, unlike other non-Hodgkin lymphomas, complete surgical excision for localized disease is an important part of the management of these patients. In this paper, we share our recommendations for a multidisciplinary team approach to the diagnosis, workup, and treatment of BIA-ALCL in line with consensus guidelines by the National Comprehensive Cancer Network.

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