Introduction: Signaling through JAK1 and/or JAK2 is common among tumor and non-tumor cells within peripheral and cutaneous T cell lymphomas (PTCL and CTCL). We conducted a phase II study of the JAK1/2 inhibitor, ruxolitinib, in patients (pts) with PTCL and CTCL and assessed the predictive value of genetic, immunohistochemical (IHC) and multiparametric immunofluorescence (mIF) biomarkers of JAK/STAT pathway activation for ruxolitinib response.
Methods: This is an investigator-initiated multi-center phase II study for pts with relapsed or refractory (RR) PTCL or CTCL following at least 1 systemic therapy. Biopsies from each patient were subjected to next-generation sequencing for JAK1, JAK2, STAT3, STAT5 and other relevant genes along with IHC assessment for phosphorylated STAT3 (pSTAT3). Pts enrolled into biomarker-defined cohorts: 1) activating JAK and/or STAT mutations (allele frequency of 0.1 or greater); 2) no JAK/STAT mutation but ≥ 30% pSTAT3 expression among tumor cells by IHC; or 3) neither. Pts received treatment with ruxolitinib 20 mg BID until progression and were assessed for response after cycles 2, 5 and every three cycles thereafter. Tissue samples collected at baseline, on-treatment, and at progression were collected and assessed by mIF (Vectra platform, HALO analysis) using markers specific for lymphoma subtype, macrophage activation, JAK/STAT and PI3 kinase signaling.
Results: The study completed enrollment with 53 pts, including 18 in cohort 1, 14 in cohort 2, and 21 in cohort 3. Cohort 3 includes 10 pts for whom JAK/STAT characterization is pending. Disease histologies per cohort are detailed in table 1. Treatment-related serious adverse events included HSV-1 stomatitis (n=1), spontaneous bacterial peritonitis (n=1), febrile neutropenia (n=3), and herpes zoster (n=1). Additional grade 3 or 4 drug-related adverse events affecting >1 pt included neutropenia (n=13), anemia (n=8), thrombocytopenia (n=5), and lymphopenia (n=3).
Among the 53 pts, 4 have not yet reached first response assessment and 1 withdrew consent following only 1 week of treatment; therefore 48 are evaluable for response. Among 48 pts, there were 3 (6%) complete responses, 8 (17%) partial responses, and 6 (12.5%) with cytopenia improvement and disease stabilization lasting more than 6 months (SD>6 mo). Overall response rate (ORR) was 23% and overall clinical benefit rate (CBR) (ORR plus SD>6 mo) was 35%. Median duration of response was 7.3 months (range 1.3-26.1 months). ORRs in cohorts 1, 2 and 3 were 28%, 31%, and 12% (cohorts 1&2 vs 3, p=0.28). CBRs in cohorts 1, 2 and 3 were 44%, 46%, and 18% (cohorts 1&2 vs. 3, p=0.07) (table 2). More frequent responses were observed in the following histologies: angioimmunoblastic T cell lymphoma, peripheral T cell lymphoma with T-follicular helper phenotype, T-cell prolymphocytic leukemia, and large granular lymphocyte leukemia (table 3).
Nine pre-treatment biopsies were analyzed by mIF from 4 ruxolitinib responders and 5 non-responders. The most notable finding was that responders to ruxolitinib had markedly lower pS6 expression within tumor cells of pre-treatment biopsies (mean pS6 expression 9.03 +/- 4.8 vs 48.19 +/- 6.6 for nonresponders; p=0.0027). In a patient with prolonged CR on ruxolitinib, progression biopsy was characterized by a marked increase in tumor cell pS6 staining. Additional samples are being analyzed and updated results will be reported at the meeting.
Conclusion: The JAK1/JAK2 inhibitor ruxolitinib is a well-tolerated and readily available therapy for pts with relapsed/refractory PTCL and CTCL. Among patients with IHC and/or genetic evidence of JAK/STAT activation, ruxolitinib has similar efficacy to approved agents for relapsed/refractory T-cell lymphoma. The association between pS6 expression and response to ruxolitinib suggests that active PI3K/mTOR signaling confers intrinsic and acquired resistance to ruxolitinib.
Moskowitz:ADC Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Erytech Pharma: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Merck: Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Cell Medica: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Cell Medica: Consultancy; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Erytech Pharma: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Incyte: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Takeda Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Cell Medica: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy; Incyte: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Erytech Pharma: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Cell Medica: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; ADC Therapeutics: Consultancy; Incyte: Research Funding; Incyte: Research Funding; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Erytech Pharma: Consultancy; Erytech Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Cell Medica: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Merck: Research Funding; Takeda Pharmaceuticals: Consultancy; miRagen Therapeutics Inc: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Jacobsen:Acerta: Consultancy; Novartis: Research Funding; Astra-Zeneca: Consultancy; F. Hoffmann-LaRoche: Research Funding; Merck: Consultancy, Research Funding; Takeda: Honoraria; Pharmacyclics: Research Funding. Ruan:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; Kite: Consultancy; Juno: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Geyer:Amgen: Research Funding; Dava Oncology: Honoraria. Noy:Medscape: Honoraria; Janssen: Consultancy; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Straus:Elsevier (PracticeUpdate): Consultancy, Honoraria; Hope Funds for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Weinstock:Celgene: Research Funding. Horwitz:Aileron: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Kura: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron: Research Funding; Trillium: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Miragen: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Forty-Seven: Research Funding; Portola: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy; Miragen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Astex: Consultancy; Astex: Consultancy; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Forty-Seven: Research Funding; Mundipharma: Consultancy; Celgene: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; Kyowa Hakko Kirin: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Research Funding; Aileron: Research Funding; Kura: Consultancy; Miragen: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; Portola: Consultancy; Forty-Seven: Research Funding; Innate Pharma: Consultancy; Affimed: Consultancy; Affimed: Consultancy.
Off-label use of ruxolitinib for T-cell lymphoma will be discussed
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