scholarly journals Dynamics of the Cutaneous T Cell Lymphoma Microenvironment in Patients Treated with Pembrolizumab Revealed By Highly Multiplexed Tissue Imaging

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1521-1521 ◽  
Author(s):  
Christian M. Schuerch ◽  
Darci J. Phillips ◽  
Salil S. Bhate ◽  
Graham L. Barlow ◽  
Steven P Fling ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Tumor Cells ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Predictive Biomarkers ◽  
Tissue Imaging ◽  
Cellular Interactions ◽  
Cutaneous T Cell Lymphoma ◽  
Advisory Committees

Cutaneous T cell lymphoma (CTCL) is a CD4+ T cell malignancy of the skin with heterogeneous outcomes and limited treatment options. Monoclonal antibodies directed against PD-1, such as pembrolizumab, have shown impressive efficacy in multiple advanced malignancies, and are currently tested in clinical trials in patients with CTCL. Initial data indicate that about half of the patients experience treatment response, whereas the other half are non-responders. Non-responders can be further divided into patients with stable disease versus rapid progressors. It is currently unknown why some CTCL patients respond to pembrolizumab while others rapidly progress, and no predictive biomarkers are available. Single-cell analysis approaches to identify biomarkers of response, for example quantifying the expression of PD-1 on tumor cells vs. reactive immune cells, have not enabled stratification of patients. We therefore hypothesized that more complex spatial cellular interactions within the immune tumor microenvironment (iTME) of CTCL could provide insight into the mechanisms of pembrolizumab response and enable prediction. We applied CODEX (CO-Detection by indEXing) highly multiplexed tissue imaging to study the CTCL iTME in matched biopsies before and after pembrolizumab therapy in 7 responders and 7 non-responders (see the Figure). Using 54 markers simultaneously allowed discriminating malignant CD4+ tumor cells from reactive CD4+ T cells and identified 30 different cell clusters with spatial information, including an M2 macrophage cluster that was enriched in non-responders before therapy. Unexpectedly, in pembrolizumab responders compared to non-responders, PD-1 expression levels were higher in multiple clusters of tumor cells and reactive T cells. Computational spatial analysis revealed ten distinct, conserved cellular neighborhoods in the CTCL iTME that changed in composition and frequency during therapy. Interestingly, one cellular neighborhood to be presented dramatically increased after therapy only in responders. Therefore, highly multiplexed spatial analysis of the CTCL iTME allows discovering novel, predictive biomarkers of immunotherapy response and will pave the way for future studies that functionally address the identified cell types and cellular interactions. Disclosures Khodadoust: Corvus Pharmaceuticals: Research Funding. Kim:miRagen: Research Funding; Merck: Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Soligenix: Research Funding; Forty Seven Inc: Research Funding; Neumedicine: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Elorac: Research Funding; Galderma: Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding. Nolan:Akoya Biosciences Inc.: Consultancy, Equity Ownership, Patents & Royalties.

scholarly journals Bnz-1, a Selective γ-Chain Cytokine Inhibitor Has Clinical Activity in Patients with Cutaneous T Cell Lymphoma By Selectively Blocking IL-2, IL-15 and IL-9 Signaling: Results of a Multicenter, Open-Label Phase 1 Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1557-1557
Author(s):  
Christiane Querfeld ◽  
Basem M. William ◽  
Jonathan E. Brammer ◽  
Lubomir Sokol ◽  
Yutaka Tagaya ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Cutaneous T Cell Lymphoma ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase

Background: Cutaneous T cell lymphoma is incurable with current therapies and there is an urgent need for more effective therapies. BNZ-1 is a pegylated peptide antagonist that binds to the common γc signaling receptor for the cytokines IL-2, IL-9 and IL-15. These cytokines, particularly IL-2 and IL-15, have been implicated in the pathogenesis of CTCL through activation of JAK/Stat signaling pathways, Therefore, we hypothesized that inhibition of the IL-2 and IL-15 signaling pathways in CTCL will induce antitumor activity in patients with CTCL. Methods: A multicenter, open-label Phase 1 study is ongoing to characterize the safety and tolerability of BNZ-1 (NCT03239392). Patients with a diagnosis of mycosis fungoides (MF) of any stage or Sézary syndrome (SS) are eligible for this trial. Pts are enrolled in sequential dose cohorts of 0.5 mg/kg, 1mg/kg, 2 mg/kg, and 4 mg/kg to receive intravenous dose of BNZ-1 to characterize safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity. Infusions are administered weekly for four doses to evaluate for safety. Thereafter, patients are enrolled on an extension phase for 3 months of weekly dosing of BNZ-1. If patient attain a response, they are eligible for a long-term extension arm, as approved by the FDA. Blood samples are collected to assess the impact of BNZ-1 on the anti-tumor response. Results: pts with MF/SS (11 M/5F, median age 61 years, range 32-89) have been enrolled. Clinical stages include IB (n=6), IIA (n=1), IIB (n=6), IVA1 (n=2), IVB (n=1). Patients were previously treated with a median of 2 ( 1-5) topical therapies and 3 (1-11) systemic therapies. Single and sequential doses of weekly 1 mg, 2 mg, or 4 mg BNZ-1 infusions have been well tolerated. The most frequently reported adverse events were pruritus (n=9), fatigue (n=5) and dry skin (n=3). All treatment-related AEs were Grade 1 or 2 in severity. No SAEs or dose limiting toxicity have been observed to date. Notably reductions in mSWATs and CAILs was noted even in patients with advanced stage disease and/or with features of large cell transformation and folliculotropic subtype. Flow cytometry of peripheral blood at baseline and during treatment indicated activation of anti-lymphoma immune responses associated with the downregulatio of PD1. Concommittantly, excess expression of cytotoxic granules (perforin & Granzyme B) has been downregulated, suggesting the silencing of inflammatory T-cell responses. Conclusions: These preliminary Phase 1 results suggest that pegylated BNZ-1 is well-tolerated and inhibition of IL-2 and IL-15 leads to clinical improvement in patients with CTCL. Evidence for the rejuvenation of anti-lymphoma immunity and a decreasing inflammatory responses was seen in cases showing clinical response consistent with our hypothesis. An expansion cohort in CTCL is currently underway to validate these promising early results. Disclosures Querfeld: Trillium: Consultancy, Other: Investigator, Research Funding; Soligenix: Other: Investigator; Celgene: Other: Investigator, Research Funding; Medivir: Consultancy; Elorac: Other: Investigator, Research Funding; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; City of Hope Cancer Center and Beckman Research Institute: Employment. William:Techspert: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Guidepoint Global: Consultancy; Defined Health: Consultancy. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Sokol:EUSA: Consultancy. Tagaya:Bioniz: Research Funding; Bioniz: Membership on an entity's Board of Directors or advisory committees. Frohna:Bioniz: Employment. Azimi:Bioniz: Employment. Zain:Seattle Genetics: Honoraria, Speakers Bureau; spectrum: Honoraria.

scholarly journals Evaluation of Symptom and Side Effect Bother in Cutaneous T-Cell Lymphoma Patients Treated with Mogamulizumab or Vorinostat

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3592-3592 ◽  
Author(s):  
Stacie Hudgens ◽  
Pierluigi Porcu ◽  
Pietro Quaglino ◽  
Auris Huen ◽  
Lysbeth Floden ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Side Effect ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Precision Oncology ◽  
Cutaneous T Cell Lymphoma ◽  
Advisory Committees ◽  
Skin Symptoms

Abstract OBJECTIVES: To determine whether individual items on patient-reported outcome measures show significant differences over the course of treatment for patients with cutaneous T-cell lymphoma (CTCL). METHODS: A large, open-label, multi-center, randomized, Phase 3 study compared mogamulizumab, an anti-C-C chemokine receptor type 4 (CCR4)-targeted antibody, versus vorinostat in 372 CTCL patients who had failed ≥ 1 prior systemic therapy. Clinical quality of life (QoL) measurements included Skindex-29, Functional Assessment of Cancer Therapy-General (FACT-G), and two measures of pruritus (a Likert Scale and ItchyQoL). Analyses on identified individual symptom items of Skindex-29 and toxicity items of FACT-G were conducted using longitudinal generalized estimation equations (GEE) of the post-baseline, treated period assessments (through Cycles 5 or 6, depending on collection schedule) for these items. The proportion of patients experiencing a 1-grade improvement is presented in terms of frequency and percentage by treatment arm. Forest plots of odds ratios (OR) and associated confidence intervals (CI) from the GEE analyses were generated to characterize the likelihood of a 1-grade categorical improvement (eg, improvement by 1 category on the verbal response scale) on individual items for patients treated with mogamulizumab compared to vorinostat during the first 6 cycles of therapy. RESULTS: The likelihood of patients experiencing a 1-grade improvement in skin symptoms, side effect bother, and lack of energy was higher for patients treated with mogamulizumab compared to vorinostat (OR > 1.0). Patients treated with mogamulizumab were more likely to observe a 1-grade improvement in painful skin (OR=1.74, CI=1.180-2.572), irritated skin (OR=1.34, CI=0.909-1.978), lack of energy (OR=2.20, CI=1.461-3.309), side effect bother (OR=1.28, CI=0.810-2.020), and general cancer pain (OR=1.38, CI=0.922-2.063) within 6 cycles of therapy (Figure). The single item descriptive and proportion analysis of 1+ grade improvement at cycle 5 from baseline is presented (Table). CONCLUSIONS: These data provide detailed information on the cumulative probability of categorical improvement of individual items on the skin symptoms of Skindex-29 and the toxicity bother, energy, and pain items of FACT-G. These results support symptom benefit of mogamulizumab over the course of treatment compared to vorinostat. Disclosures Porcu: Innate Pharma: Consultancy. Leoni:Kyowa Kirin: Employment. Duvic:Oncoceuticals: Research Funding; Precision Oncology, LLC: Membership on an entity's Board of Directors or advisory committees; MiRagen Therapeutics: Consultancy; UT MD Anderson Cancer Center: Employment; Aclaris Therapeutics Int'l Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Defined Health: Consultancy; Jonathan Wood & Associates: Other: Speaker; Allos: Research Funding; Array Biopharma: Consultancy, Honoraria; Cell Medica Inc.: Consultancy, Honoraria; Concert Pharmaceuticals, Inc.: Consultancy; Guidepoint Global: Consultancy; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity's Board of Directors or advisory committees; Shape: Research Funding; Medscape: Other: Speaker/Preceptor; Huya Bioscience Int'l: Consultancy; Eisai: Research Funding; Dr. Reddy's Laboratories (A.K.A. Promius Pharma): Consultancy; Forty Seven, Inc.: Membership on an entity's Board of Directors or advisory committees; Clinical Care Options: Consultancy; Huron Consulting Group: Consultancy; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Soligenix, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kiniksa Pharmaceuticals: Consultancy; The Lynx Group: Consultancy; Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEDACorp: Consultancy; Medivir AB: Membership on an entity's Board of Directors or advisory committees; Taiwan Liposome Company LTD: Consultancy; Evidera, Inc.: Consultancy; Rhizen Pharma: Research Funding; Spatz Foundation: Research Funding; Tetralogics: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Resistance to Mogamulizumab Is Associated with Loss of CCR4 in Cutaneous T Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1325-1325
Author(s):  
Sara Beygi ◽  
Sebastian Fernandez-Pol ◽  
George Duran ◽  
Youn H. Kim ◽  
Michael S. Khodadoust
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Mycosis Fungoides ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Sézary Syndrome ◽  
Sezary Syndrome ◽  
Cutaneous T Cell Lymphoma ◽  
Advisory Committees

Abstract Background: Mogamulizumab is a humanized anti-CCR4 antibody approved for the treatment of mycosis fungoides and Sézary Syndrome. Despite almost universal expression of CCR4 in these diseases, many patients eventually develop resistance to mogamulizumab (moga). The mechanisms of resistance to moga have not been characterized. An understanding of the resistance mechanisms will shed light on the disease biology and inform selection of next line therapies and the development of future CCR4-directed treatments for patients with cutaneous T cell lymphoma (CTCL). Methods: We identified 19 patients with mycosis fungoides or Sezary syndrome in whom moga had been discontinued due to lack or loss of response to therapy. Archival blood and skin and/or lymph node biopsies after discontinuation of treatment were studied. Specimens collected prior to initiation of moga were also procured whenever available. CCR4 protein expression was determined by immunohistochemistry (IHC; clone L291H4; Biolegend). Targeted sequencing was performed using the Agilent XTHS2 platform (Agilent) with a custom Agilent SureSelect panel that included full coverage of the exonic regions of CCR4. Results: Fourteen patients had Sézary syndrome and five had mycosis fungoides. Twelve patients were classified as primary refractory to treatment and the remaining seven patients had secondary resistance. Median duration of treatment with moga was 3.5 months (range: 2-41). CCR4 expression was non-detectable in post-treatment specimens of 8 of 14 (57%) patients with evaluable specimens. Targeted DNA sequencing of post-treatment samples revealed novel coding mutations of CCR4 in three patients. Only one of the 3 mutations (L21V) overlapped with the known N-terminal mogamulizumab binding epitope. The other two mutations occurred in transmembrane domains (M116R, T161-W162 delinsSR). Two patients with mutations in CCR4 also had unequivocal copy number loss involving the CCR4 locus. Acquisition of CCR4 genomic alterations corresponded with lack of CCR4 expression by immunohistochemistry. In-vitro validation of the novel CCR4 mutations is ongoing and results from these experiments will be included in the final presentation. Conclusion: Overall our study indicates that potential loss of CCR4 expression, with or without underlying genomic aberrations, represents a major hurdle in the development of future CCR4 targeting strategies in CTCL. This finding has important implications for management and monitoring of cutaneous T cell lymphoma patients receiving CCR4 directed therapies. Disclosures Beygi: Kite/Gilead: Current Employment. Kim: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CRISPR: Research Funding; Eisai: Research Funding; Soligenix: Research Funding; Portola: Membership on an entity's Board of Directors or advisory committees, Research Funding; Elorac: Research Funding; Galderma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Corvus: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Secura Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding. Khodadoust: Alexion, AstraZeneca Rare Disease: Other: Study investigator; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding.

Response Of Rare Variants Of Cutaneous T Cell Lymphoma (CTCL) To Treatment With Bexarotene. A Prospective German DeCOG Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4379-4379 ◽  
Author(s):  
Michael Weichenthal ◽  
Simone Goldinger ◽  
Ulrike Wehkamp ◽  
Marc Beyer ◽  
Annette Stein ◽  
...  
Keyword(s):  
T Cell ◽  
Treatment Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Rare Variants ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Advisory Committees ◽  
Travel Costs

Abstract The Retinoid-X-Receptor specific retinoid bexarotene is approved for treatment of cutaneous T-cell lymphoma (CTCL) in the United States and Europe. CTCL is a heterogeneous group of peripheral non-Hodgkin lymphomas with different prognosis and different response to treatment and the current WHO classification contains nine different entities with Mycosis fungoides (MF) as the most common subtype. Since most data on efficacy and tolerability are available from studies with MF, this Dermatologic Cooperative Oncology Group (DeCOG) trial (ADO-CTCL-3) evaluates treatment response to bexarotene in patients with non-MF CTCL, encompassing CD30+ primary cutaneous ALCL and severe lymphomatoid papulosis (LyP), CD-30 negative pleomorphic TCL, Sezary's syndrome (SS), subcutaneous panniculitis-like TCL, and other defined variants. Additionally, patients with different rare variants of MF, including folliculotropic (fMF), granulomatous, erythrodermic, and CD30+ transformed MF were included. 200 patients with CTCL stage IB or higher and at least one prior treatment failure were registered in this trial with bexarotene at an initial daily dose of 150mg/m² orally und prophylactic fenofibrate medication. Bexatrotene was increased to a target dosage of 300 mg/m² in patients with tolarable serum lipids under these conditions. Patients were evaluated according to a standardized evaluation tool (tumor burden index; TBI) up to 24 weeks of of treatment or until progression occured. In responding patients, treatment could be continued until progression. After a central pathology board review process 2 patients needed to be excluded from evaluation because of misdiagnoses. Additional 11 patients could not be evaluated for response due to early withdrawal. Among the remaining patients there were 18 patients with SS, 8 cutaneous CD30+ ALCL, 10 Lyp, 9 other rare entities. In addition MF cases with folliculotropic subtype (18), CD30+ transformation (11), CD30- transformation (4), and a variety of other MF subtypes could be compared to the response in classical MF. Response to bexarotene could be confirmed in classical MF with an objective response (OR) rate of 37 percent (5% CR; 32% PR). Response rates for the other entities were as follows: CD30+ ALCL 50% OR, LyP 60% OR, SS 33% OR, other forms of CTCL together 33% OR. In MF with CD30+ transformation 46% responded, in contrast to only 11% of cases with folliculotropic MF. Tolerability was as expected with most grade III/IV toxicities limited to hyperlipidemia. Side effect management anf the incidence of serious adverse events could be substantially improved using standard algorithms for lipid control. In conclusion, this is one of the largest CTCL cohorts with exact pathological review worldwide evaluated for treatment response with bexarotene. Bexarotene appears to be a safe and effective treatment option also in non-classical MF and CTCL variants. Folliculotropic MF proved to be a difficult-to-treat entity and CD30 expression seems to be a favourable prognostic marker for treatment response. Disclosures: Weichenthal: Cephalon GmbH: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; TEVA GmbH: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Goldinger:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Wehkamp:TEVA GmbH: Travel costs Other. Beyer:TEVA GmbH: Honoraria, Research Funding; Cephalon GmbH: Honoraria, Research Funding. Stein:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Tsianakas:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Koch:Cephalon: Travel costs Other. Yazdi:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Wobser:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Frambach:Cephalon: Travel costs Other; TEVA: Travel costs, Travel costs Other. Dippel:Cephalon GmbH: Honoraria, Travel costs Other; TEVA GmbH: Honoraria, Travel costs, Travel costs Other. Geißler:Cephalon GmbH: Travel costs Other; TEVA GmbH: Travel costs, Travel costs Other. Loquai:TEVA GmbH: Travel costs Other. Kurschat:Cephalon: Travel costs Other; TEVA GmbH: Honoraria, Travel costs, Travel costs Other. Pföhler:Cephalon: Travel costs Other. Hartmann:Cephalon GmbH: Travel costs Other; TEVA GmbH: Travel costs, Travel costs Other. Coors:Cephalon GmbH: Travel costs Other; TEVA GmbH: Honoraria, Travel costs, Travel costs Other. Hallermann:TEVA GmbH: Travel costs Other. Mohr:TEVA: Honoraria, Travel costs Other. Hillen:TEVA: Travel costs Other. Belloni:Cephalon GmbH: Travel costs Other. Mitteldorf:Cephalon: Travel costs Other. Assaf:TEVA: Honoraria, Research Funding, Travel costs Other. Klemke:TEVA GmbH: Consultancy, Honoraria; Cephalon GmbH: Honoraria. Becker:Cephalon GmbH: Honoraria, Research Funding; TEVA GmbH: Honoraria. Dummer:Cephalon GmbH: Honoraria, Research Funding; TEVA GmbH: Honoraria. Nicolay:TEVA: Travel costs Other.

scholarly journals Development of a Pathway-Directed Drug Screen Platform for Cutaneous T Cell Lymphoma Using Patient-Derived Xenograft Models

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1578-1578
Author(s):  
CHI-HENG WU ◽  
Chen-Yen Yang ◽  
Linlin Wang ◽  
Hua-Xin Gao ◽  
Rakhshandehroo Taha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Tumor Burden ◽  
Cutaneous T Cell Lymphoma ◽  
Advisory Committees ◽  
Patient Derived Xenograft ◽  
Pdx Model

Cutaneous T cell lymphoma (CTCL) is an orphan disease and represents 3% of non-Hodgkin lymphomas. Mycosis fungoides and Sézary syndrome (MF/SS) are the most common subtypes of CTCL. The development of targeted therapies for orphan diseases is challenging, but particularly so in the case of MF/SS due to the lack of reliable preclinical models for this malignancy, which is limited to the skin at the early stage, but disseminated to lymph nodes and other organs as disease progresses. Here we report a novel patient-derived xenograft (PDX) mouse model of MF/SS that recapitulates the multi-compartmental nature of CTCL and a blood-based genetic biomarker assay for quantitative monitoring of systemic tumor burden in PDX mice. The PDX models were extensively characterized and exhibit cardinal clinical and histologic features of CTCL, including erythematous scaly skin lesions and eventual lymphomatous dissemination to the spleen and other organs, and maintain the molecular characteristics of their clinical counterparts. The malignant T cells harvested from spleen of PDX mice shared identical TCR sequences and immunophenotypes with corresponding MF/SS patient donor, which featured as losing CD7 and CD26 expression in CD4+ T cells. We also developed a quantitative assay of tumor burden in PDX mice by determining the amount of human β-actin cell-free DNA (cfDNA) in the plasma. The cfDNA levels in the plasma were increased in a linear fashion and correlated with the tumor growth post-implantation. To explore the utility of this PDX model for drug testing, we searched for novel agents for CTCL by performing a high-throughput screen of selected available targeted agents and identified phosphatidylinositol 3-kinase (PI3K) as a high value target. A PI3K inhibitor was advanced to our PDX model with favorable results including disease attenuation and survival prolongation. Further experiments using isoform-specific siRNA knockdowns and isoform-selective PI3K inhibitors identified PI3K-δ as the tumor-driving isoform. Additional studies showed synergistic combination of PI3K-δ inhibitors with histone deacetylase (HDAC) inhibitors. The particularly potent combination of copanlisib and panobinostat is proposed for further clinical development. Disclosures McCormick: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aduro BioTech,Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; BridgeBio Pharma,Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Stock;Ownership; Caris Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo Co., Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; NeuroTrials,LLC: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences,Inc.: Research Funding; Leidos Biomedical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Navire: Membership on an entity's Board of Directors or advisory committees, Other: Stock;Ownership; Riptide Bioscience: Membership on an entity's Board of Directors or advisory committees; Quadriga Biosciences: Membership on an entity's Board of Directors or advisory committees; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PMV Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer,Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ai:Nurix Inc: Research Funding; ADC Therapeutics: Honoraria; Bayer: Honoraria; BMS: Honoraria; Kirin: Honoraria; Immune Design: Honoraria; Seattle Genetics: Honoraria.

scholarly journals Efficient Targeting of CD38 in Mature T-Cell Neoplasms with Daratumumab and Allogeneic NK Cells

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2408-2408
Author(s):  
William T. Johnson ◽  
Colleen Isabelle ◽  
Ashley N Vogel ◽  
Jonathan E Brammer ◽  
Amy E Boles ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Board Of Directors ◽  
Tumor Cells ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Advisory Committees ◽  
Cd38 Expression

Abstract Introduction: Mature T-cell neoplasms (MTCN) are a heterogeneous and aggressive group of lymphoid neoplasms with very limited options for precision immunotherapy. Targeted immunotherapy with antibodies directed against surface markers on tumor cells has emerged as an effective treatment for B-cell neoplasms, but the development of immunotherapy strategies for MTCN has been much slower. CD38 is expressed at low levels in a subset of normal resting T-cells. Data on the frequency and level of CD38 expression is MTCN are lacking. Our goal was to study the expression and stability of CD38 on a spectrum of neoplastic T-cell populations and assess the potential anti-tumor effect of anti-CD38 monoclonal antibodies in combination with allogeneic natural killer (NK) cells in MTCN. Methods and results: We searched the Thomas Jefferson University Hospital (TJUH) pathology records for all cases of MTCN for which immune-phenotypical characterization of the neoplastic T-cell population by multi-color flow cytometry (FC) was available. CD38 expression was evaluated in cases where an abnormal T-cell population (defined as loss of one on more pan T-cell markers and/or a skewed CD4 to CD8 ratio). A total of 103 unique patients with MTCN were identified. Of these, 51 had at least one biopsy whereby tumor cells had an abnormal immunophenotype which could then be assessed for CD38 expression. CD38 was expressed to some extent in all but 2 cases with expression levels on peripheral T-cell lymphoma-not other specified (PTCL-NOS)(% Mean±SEM = 80.84±10.26, N=11), angioimmunoblastic T-cell lymphoma (AITL) (% Mean±SEM = 80.56±7.34, N=6), nodal PTCL with T follicular-helper (T FH) phenotype (% Mean±SEM = 55.00±12.72, N=7), anaplastic large cell lymphoma (ALCL) (% Mean±SEM = 77.38±10.75, N=3), large granular lymphocytic leukemia (LGLL) (% Mean±SEM = 80.27±7.49, N=4), T-cell prolymphocytic leukemia (T-PLL) (% Mean±SEM = 88.26±4.20, N=7), cutaneous T-cell lymphoma (CTCL) (% Mean±SEM = 49.52±14.77, N=7), adult T-cell leukemia/lymphoma (ATLL) (% Mean±SEM = 76.68±10.45, N=3), hepatosplenic T-cell lymphoma/monomorphic epitheliotropic intestinal T-cell lymphoma (HSTCL/MEITL) (% Mean±SEM = 75.00±11.37, N=3). The medians and ranges of the MFI of CD38 on CD38+ tumor cells were the following: PTCL-NOS 29.46 (3.1-115.62), AITL 13.64 (2.67-29.41), other PTCL-T FH 5.87 (0-48.67), ALCL 11.13 (3.6-11.28), LGL (13.52 (9.72-18.25), T-PLL 6.49 (3.09-18), CTCL 8.36 (0-116.75), ATLL 27.17 (3.54-60.5), HSTCL/MEITL 15.96 (6.96-167.85). We also measured surface expression of CD38 on the patient-derived MTCN cell lines HuT-78, HuT-102, Jurkat, H9, HH, and MOTN1, all of which expressed CD38, to determine which of these cell lines could be used for in vitro experiments. We next evaluated if the CD38 molecule is an effective target for antibody-mediated therapy in MTCN, by testing the ability of daratumumab (dara) to enhance antibody-dependent cellular cytotoxicity (ADCC) elicited by NK cells. For this, we purified normal NK-cells from TJUH Blood Bank leukoreduction filters and cultured with recombinant IL-15 for 48 hours prior to all experiment. T-cell lines and primary MTCN cells were treated with increasing concentrations (0.1 µg/mL - 2 µg/mL) of dara or isotype control. NK-cells were added at Effector:Target ratio of 5:1 and incubated for 4 hours at 37⁰ Celsius. Cytotoxicity was measured by LDH release assay. Dara induced significant cell lysis starting at doses as low as 0.1μg/mL in both T-cell lines and primary MTCN cells, reaching maximum cytotoxicity at 0.5-2μg/mL (mean±SEM cytotoxicity in isotype vs dara treated cells= 50.0±5.05% vs 97.5±2.5%, N=4, p-value=0.0002). The degree of ADCC induction also correlated with interferon-gamma (IFN-g) release by NK cells in vitro for both T-cell lines and primary MTCN cells. Conclusions: The majority of MTCN analyzed (N=49, 96%) showed any degree of CD38 expression by FC with a wide variation of intensity, including within the same subtype. Allogeneic NK cells efficiently elicited dara-mediated ADCC of tumor cells from all MTCN subtypes and produced abundant IFN-g. These data highlight the potential of targeting CD38 in MTCN with anti-CD38 antibodies and allogeneic NK cells. The strong CD38 expression observed in most tumor cells from ultra-rare and very aggressive subtypes of MTCL opens the door to much needed new treatment strategies. Disclosures Brammer: Celgene: Research Funding; Kymera Therapeutics: Consultancy; Seattle Genetics: Speakers Bureau. Chakravarti: Kiadis Pharma: Patents & Royalties. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

scholarly journals Final Results of Phase 1/1b Study of Tenalisib, Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2831-2831 ◽  
Author(s):  
Swaminathan P. Iyer ◽  
Brad M. Haverkos ◽  
Jasmine Zain ◽  
Radhakrishnan Ramchandren ◽  
Mary Jo Lechowicz ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advisory Committees

Introduction: Tenalisib (RP6530) is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. PI3K plays a critical role in T-cell development and activation and several studies have validated the PI3K-AKT pathway as a potential therapeutic target in T cell lymphomas. Preliminary results of the ongoing Phase 1/1b T-cell lymphoma (TCL) study demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (Oki, ASCO 2018 and Iyer, ASH 2018). We now present the final results of the study (NCT02567656). Methods: This study comprised of four-dose escalation cohorts, followed by two dose expansion cohorts at MTD enrolling 20 patients each in PTCL and CTCL cohorts. Patients had histologically confirmed TCL, ECOG PS ≤2, and had received ≥1 prior therapy. Patients received Tenalisib [200 mg BID-800 mg BID (fasting), 800 mg (fed only)] orally until progression or unacceptable toxicity. The primary objectives were to determine the MTD and pharmacokinetic profile. The secondary objective was to evaluate overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and mSWAT respectively. Adverse events were graded according to CTCAE v4.03. Results: Fifty-eight patients were enrolled in study, 19 in dose escalation and 39 in dose expansion (28 PTCL and 30 CTCL). Median number of prior therapies was 4 (range, 1-15). Safety assessment of 58 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. Treatment related Grade≥3 AEs were elevated ALT/AST (21%), rash (5%), and hypophosphatemia (3%). These events were reversible and managed by withholding study drug. Additionally, in few patients (N=9), steroids were used to manage elevated ALT/AST. There were six treatment related serious adverse events, none of these led to fatal outcome. At end of the study, four (3 CTCL; 1 PTCL) patients who completed minimum 8 cycles of therapy were rolled over to a compassionate use study (NCT03711604) and were followed up. Efficacy assessments demonstrated an ORR of 46% (3 CR and 13 PR) and clinical benefit rate (CR+PR+SD) of 77%. Subset efficacy analysis showed an ORR in PTCL of 47% (3 CR; 4 PR) and in CTCL of 45% (9 PR). The median time to initial response was 1.8 months and was similar in both sub-types. The overall median DOR was 4.91 months (range 0.9-26.6); in PTCL patients the DOR was 6.53 months, (range: 0.97-21.0) and 3.8 months (range: 1.67-25.67) in CTCL patients. In 3 PTCL patients who achieved CR, the median DOR was 19.5 months (range 7.5-21). Conclusion: Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL. Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population. Disclosures Iyer: Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Dermira: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Routhu:Rhizen Pharmaceuticals S.A.: Employment. Barde:Rhizen Pharmaceuticals S.A.: Employment. Nair:Rhizen Pharmaceuticals S.A.: Employment. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding.

Final Results From a Pivotal, Multicenter, International, Open-Label, Phase 2 Study of Romidepsin In Progressive or Relapsed Peripheral T-Cell Lymphoma (PTCL) Following Prior Systemic Therapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 114-114 ◽  
Author(s):  
Bertrand Coiffier ◽  
Barbara Pro ◽  
H. Miles Prince ◽  
Francine M Foss ◽  
Lubomir Sokol ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Systemic Therapy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Open Label ◽  
Advisory Committees ◽  
Prior Systemic Therapy

Abstract Abstract 114 Background: Romidepsin is a potent HDAC inhibitor approved by the FDA for patients (pts) with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. Durable clinical benefit and tolerability of romidepsin in pts with recurrent or refractory PTCL have been previously observed in a phase 2 trial conducted by the National Cancer Institute. The aim of this phase 2, single-arm, open-label registration study was to evaluate the activity of romidepsin in a larger number of pts with progressive or relapsed PTCL. Methods: Pts with histologically confirmed PTCL (PTCL NOS, angioimmunoblastic T-cell lymphoma, ALCL [ALK-1 negative], other subtypes) who failed or were refractory to ≥ 1 prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Exclusions included inadequate bone marrow or other organ function and significant cardiovascular abnormalities. Pts received romidepsin 14 mg/m2 as a 4-h IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for stable disease (SD) or response. The primary endpoint was rate of complete response (CR + CRu) as evaluated by a central Independent Review Committee (IRC) using International Working Criteria for non-Hodgkin's lymphoma. IRC assessment consisted of a 2-step process, with initial radiographic review of images (CT, MRI) followed by an overall clinical assessment based on the radiology evaluations, photographs, and relevant clinical parameters. Secondary endpoints included objective response rate (ORR): CR + CRu + partial response (PR), investigator-assessed responses, duration of response, time to response, and safety. Results: 131 pts from 48 US, European, and Australian sites were enrolled and received at least 1 dose of romidepsin (as-treated population); 130 patients had histologically confirmed PTCL by central review. Mean age of all pts was 59.4 y (range, 20–83) and median time since diagnosis was 1.25 y (range, 0–17). Median number of prior systemic therapies was 2 (range, 1–8). 21 pts (16%) had failed a prior stem cell transplant. Responses assessed by the IRC are noted in the table below. Longest duration of response is 26+ mo and 16 (94%) of the 17 pts with a CR had not progressed as of the data cutoff (March 31, 2010). Investigator-assessed responses included 21 pts (16%) with CR + CRu, 18 pts (14%) with PR for an ORR of 30%. Currently, 13 pts continue to receive treatment (range, 10–36 cycles). Adverse events (AEs) were reported in 126 of 131 pts (96%). AEs reported in ≥ 20% of pts were nausea (59%), fatigue (41%), vomiting (38%), thrombocytopenia (38%), diarrhea (35%), pyrexia (34%), neutropenia (30%), anorexia (28%), constipation (28%), anemia (23%), and dysgeusia (21%). AEs ≥ grade 3 were reported for 86 pts (66%), with the most common (≥ 5%) being pneumonia (5%), pyrexia (5%), sepsis (5%), and vomiting (5%). 60 pts (46%) had at least 1 serious AE: the most frequently reported (≥ 5%) were pyrexia (7%), pneumonia (5%), vomiting (5%), and sepsis (5%). 22 pts (17%) withdrew due to AEs. 8 pts (6%) died within 30 days of the last dose of romidepsin; 1 death, due to sepsis, was assessed as possibly related to treatment. Conclusions: Complete and durable responses were observed with single agent romidepsin in pts with relapsed PTCL. These data support the therapeutic potential for romidepsin in relapsed PTCL and suggest that romidepsin is a strong candidate for inclusion in future novel regimens for these diseases. As of the data cutoff (March 31, 2010), the median duration of follow-up for CR is 8.2 mo. Disclosures: Coiffier: Gloucester: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Romidepsin is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Romidepsin is not currently approved for the treatment of peripheral T-cell lymphoma (PTCL). Pro:Celgene: Research Funding. Prince:Celgene: Consultancy, Honoraria, Research Funding. Foss:Celgene: Consultancy; Eisai: Consultancy, Speakers Bureau; Merck: Speakers Bureau; Allos: Consultancy, Speakers Bureau; Cephalon: Speakers Bureau. Sokol:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Caballero:Celgene: Membership on an entity's Board of Directors or advisory committees. Morschhauser:Roche: Consultancy, Honoraria; Bayer: Honoraria. Padmanabhan:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shustov:Celgene: Research Funding. Nichols:Celgene: Employment. Carroll:Celgene: Employment. Balser:Gloucester Pharmaceutical: Consultancy. Horwitz:Celgene: Consultancy, Honoraria.

Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE): First Detailed Report of Primary Treatment

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1614-1614 ◽  
Author(s):  
Francine M. Foss ◽  
Kenneth R. Carson ◽  
Lauren Pinter-Brown ◽  
Steven M. Horwitz ◽  
Steven T. Rosen ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Initial Treatment ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Primary Treatment ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Advisory Committees

Abstract 1614 Background: Registries can be invaluable for describing patterns of care for a population of patients. COMPLETE is a registry of peripheral T-cell lymphoma (PTCL) patients designed to identify the lymphoma-directed treatments and supportive care measures that PTCL patients receive. We report here the first detailed findings of initial therapy. Methods: This is a prospective, longitudinal, observational registry that is led by a global steering committee. Patients with newly diagnosed PTCL and providing written informed consent are eligible. Patients are entered into the registry from time of initial diagnosis and followed for up to 5 years. Only locked records are reported. Results: As of July 2012, 330 patients have been enrolled from the United States. The first patient was enrolled in February 2010. Locked baseline and treatment records are available for 124 and 81 patients, respectively. Of the 124 patients with locked baseline records, 67 patients (54%) were male, the mean age was 59 (range: 19–89), and race/ethnicity was recorded as: White (87 patients; 70%), Black (19; 15%), Asian (5; 4%) and other/unknown (13; 11%). Histology was reported as follows: PTCL-not otherwise specified (27%), anaplastic large cell lymphoma-primary systemic type (18%), angioimmunoblastic T-cell lymphoma (17%), transformed mycosis fungoides (7%), T/NK-cell lymphoma-nasal and nasal type (6%), adult T-cell leukemia/lymphoma, HTLV 1+ (6%) and other (19%). 25 patients (20%) had received another diagnosis, including B-cell lymphoma, Hodgkin's disease and other T-cell lymphomas, prior to their current diagnosis of PTCL. 49 patients (40%) had B symptoms, 102 patients (82%) had an Ann Arbor stage of III/IV, 116 patients (94%) had ECOG performance status of 0–1, and international prognostic index (IPI) score was distributed as follows: IPI 0 (7% of patients), 1 (15%), 2 (43%), 3 (26%), and 4 (9%). Of the 81 patients with locked treatment records, details on initial treatment can be found in table below. Conclusions: This first detailed analysis of primary treatment of PTCL indicates that this disease is still largely being treated with regimens derived primarily from studies of B-cell lymphomas and that a single standard of care does not exist. The fact that a meaningful proportion of patients were initially diagnosed with something other than their current diagnosis of PTCL points out the challenges of diagnosing the disease. While the intent of initial treatment for most patients is to affect a cure, more than 20% of patients were noted as deceased at the end of initial treatment, underscoring the need for more effective, disease-specific therapy. Disclosures: Foss: Merck: Study Grant, Study Grant Other; Celgene: Study Grant, Study Grant Other; Eisai: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Allos: Consultancy. Carson:Allos: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Pinter-Brown:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz:Allos: Consultancy, Research Funding. Rosen:Allos: Consultancy, Honoraria. Pro:Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Allos: Honoraria; Seattle Genetics: Research Funding. Gisselbrecht:Allos: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hsi:Allos: Research Funding; Eli Lilly: Research Funding; Abbott: Research Funding; Cellerant Therapeutics: Research Funding; BD Biosciences: Research Funding; Millenium: Research Funding.

Long-Term Survival and Absence of Late Relapses in Patients Who Underwent Allogeneic Stem Cell Transplantation for Advanced Cutaneous T-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5843-5843
Author(s):  
Lori A Leslie ◽  
Lori A. Leslie ◽  
Tatyana A Feldman ◽  
Alan P Skarbnik ◽  
David H. Vesole ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Cell Lymphoma ◽  
Advisory Committees ◽  
Unrelated Donors ◽  
Related Mortality

Abstract Introduction Primary cutaneous T-cell lymphomas (CTCL) are rare subtypes of extranodal non-Hodgkin lymphoma for which no conventional curative therapies are available. Patients (pts) with early-stage, limited disease typically experience an indolent course. Pts with advanced or progressive disease are more likely to experience an aggressive course characterized by short-lived responses to therapy, debilitating symptoms that significantly impact quality of life,and limited overall survival. Prior retrospective studies have shown allogeneic stem cell transplantation (alloSCT) may lead to durable remissions in pts with advanced CTCL, the largest of which included 47 pts and reported an overall survival (OS) of 51% and progression-free survival (PFS) of 26% at 4-years (Hosing et al. Ann Oncol 2015). We performed a retrospective analysis of pts who underwent alloSCT for advanced CTCL at our institution. Methods We performed a retrospective case analysis of 11 pts with CTCL who underwent alloSCT between 1/1/2008 and 3/1/2016. OS and PFS were estimated using Kaplan-Meier analysis. Other endpoints included transplant-related mortality and morbidity as well as CTCL-related mortality. Results Eleven pts were identified including 5 with mycosis fungoides/Sezary syndrome (MF/SS), 2 with CD4+ CTCL not otherwise specified (NOS), and 1 each with CD8+ CTCL-NOS, ALK-negative cutaneous anaplastic large cell lymphoma (cALCL), sub panniculitis-type T-cell lymphoma, and cutaneous smoldering HTLV-1 associated adult T-cell leukemia/lymphoma (ATLL). The median age at diagnosis was 45.4 yr, median time to alloSCT was 2.4 yr. The median follow-up post-alloSCT was 39.2 mo. Prior to alloSCT, pts received a median of 5 lines of therapy (range 2-11). Total skin electron beam radiation (TSEB) was part of the immediate pre-alloSCT regimen for 6 pts (55%), all of whom had persistent disease. Four pts (67%) converted to CR pre-alloSCT with the addition of TSEB. Nine pts (82%) received reduced-intensity and 2 pts (18%) received myeloablative conditioning. Ten pts received peripheral blood stem cells (PBSC) and 1 received bone marrow: 4 pts (36%) received stem cells from HLA-matched unrelated donors, 2 (18%) from mismatched unrelated donors, 4 (36%) from matched sibling donors, and 1 (9%) from a haploidentical sibling. Nine pts (82%) received tacrolimus/mini methotrexate and 2 pts (18%) received tacrolimus/mycophenolate mofetil for graft-versus-host disease (GvHD) prophylaxis. The pt who received haploidentical stem cells also received post-alloSCT cyclophosphamide. At the time of transplantation, disease status included: complete response (CR) in 8/11 pts (73%), partial response (PR) in 2/11 pts (18%), and progressive disease (PD) in 1/11 pts (9%). At day 100, 9/11 pts (82%) were in CR, 1 pt had PD, and 1 pt with CD8+ CTCL-NOS had died on day 26 of PD. Two of the 9 pts (22%) in CR on day 100 relapsed soon thereafter, one on day 105 and one on day 113. Both achieved CR, 1 with withdrawal of immunosuppression, 1 with salvage brentuximab vedotin, bexarotene and donor lymphocyte infusions (DLI). There were no late relapses. Median OS at 36 mo was 72% (Figure 1): 1 pt died of PD on day 26, 2 pts died of non-alloSCT/non-CTCL adverse events (cerebrovascular accident (CVA), suicide). Median PFS at 36 mo was 64% (Figure 2). Fifty percent (2/4) of pts who relapsed/progressed were in CR at time of alloSCT, 86% (6/7) of pts who did not relapse were in CR at time of alloSCT. The incidence of acute cutaneous GvHD was 100%: 30% grade 1, 70% grade 2-3. The incidence of chronic cutaneous GvHD was 50%: 2 pts (20%) have ongoing severe GvHD, 1 pt with severe DLI-induced GvHD died due to CVA, 2 pts (20%) have completed therapy with no further manifestations of chronic GvHD. There were no other significant long-term toxicities of alloSCT identified. Disease-related mortality was 9% (1/11). Transplant-related mortality was 0%. Conclusion AlloSCT is well-tolerated and may result in long-term remissions for pts with various, heavily pretreated subtypes of CTCL. In our experience relapses were uncommon, occurred early, and durable CR could again be achieved with immunomodulatory approaches. Depth of response pre-alloSCT correlated with long term PFS and OS. It is likely that TSEB may be omitted safely in pts in CR, but should be administered immediately pre-alloSCT to deepen responses in patients with persistent disease. Disclosures Leslie: Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Feldman:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Abbvie/Pharmacyclics/Janssen: Speakers Bureau. Vesole:Novartis: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Goy:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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