Signaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 biomarker-defined cohorts: (1) activating JAK and/or STAT mutations, (2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry, or (3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 of 7 patients with MF had CBR (ongoing PR > 18 months). CBR among the PTCL cases (n = 45) in cohorts 1, 2, and 3 were 53%, 45%, and 13% (cohorts 1 & 2 vs 3, P = .02), respectively. Eight patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in <25% of tumor cells was associated with response to ruxolitinib (P = .05). Our findings indicate that ruxolitinib is active across various PTCL subtypes and support a precision therapy approach to JAK/STAT inhibition in patients with PTCL. This trial was registered at www.clincialtrials.gov as #NCT02974647.

IMPORTANCEAndrogen deprivation therapy (ADT) has been theorized to decrease the severity of SARS-CoV-2 infection in patients with prostate cancer owing to a potential decrease in the tissuebased expression of the SARS-CoV-2 coreceptor transmembrane protease, serine 2 (TMPRSS2). OBJECTIVE To examine whether ADT is associated with a decreased rate of 30-day mortality from SARS-CoV-2 infection among patients with prostate cancer. DESIGN, SETTING, AND PARTICIPANTS This cohort study analyzed patient data recorded in the COVID-19 and Cancer Consortium registry between March 17, 2020, and February 11, 2021. The consortium maintains a centralized multi-institution registry of patients with a current or past diagnosis of cancer who developed COVID-19. Data were collected and managed using REDCap software hosted at Vanderbilt University Medical Center in Nashville, Tennessee. Initially, 1228patients aged 18 years or older with prostate cancer listed as their primary malignant neoplasm were included; 122 patients with a second malignant neoplasm, insufficient follow-up, or low-quality data were excluded. Propensity matching was performed using the nearest-neighbor method with a 1:3 ratio of treated units to control units, adjusted for age, body mass index, race and ethnicity, Eastern Cooperative Oncology Group performance status score, smoking status, comorbidities (cardiovascular, pulmonary, kidney disease, and diabetes), cancer status, baseline steroid use, COVID-19 treatment, and presence of metastatic disease. EXPOSURES Androgen deprivation therapy use was defined as prior bilateral orchiectomy or pharmacologic ADT administered within the prior 3 months of presentation with COVID-19. MAIN OUTCOMES AND MEASURESThe primary outcome was the rate of all-cause 30-day mortality after COVID-19 diagnosis for patients receiving ADT compared with patients not receiving ADT after propensity matching. RESULTSAfter exclusions, 1106 patients with prostate cancer (before propensity score matching: median age, 73 years [IQR, 65-79 years]; 561 (51%) self-identified as non-Hispanic White) were included for analysis. Of these patients, 477 were included for propensity score matching (169 who received ADT and 308 who did not receive ADT). After propensity matching, there was no significant difference in the primary end point of the rate of all-cause 30-day mortality (OR, 0.77; 95% CI, 0.42-1.42).

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. Disclosures 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. OffLabel Disclosure: Off-label use of ruxolitinib for T-cell lymphoma will be discussed

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

This observer study investigates the effect of computerized artificial intelligence (AI)-based decision support system (CDSS-T) on physicians’ diagnostic accuracy in assessing bladder cancer treatment response. The performance of 17 observers was evaluated when assessing bladder cancer treatment response without and with CDSS-T using pre- and post-chemotherapy CTU scans in 123 patients having 157 pre- and post-treatment cancer pairs. The impact of cancer case difficulty, observers’ clinical experience, institution affiliation, specialty, and the assessment times on the observers’ diagnostic performance with and without using CDSS-T were analyzed. It was found that the average performance of the 17 observers was significantly improved (p = 0.002) when aided by the CDSS-T. The cancer case difficulty, institution affiliation, specialty, and the assessment times influenced the observers’ performance without CDSS-T. The AI-based decision support system has the potential to improve the diagnostic accuracy in assessing bladder cancer treatment response and result in more consistent performance among all physicians.