Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata

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Abstract

BACKGROUND. Alopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8⁺ T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been systematically examined.

METHODS. This was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU). Tofacitinib (5 mg) was given twice daily for 3 months. Endpoints included regrowth of scalp hair, as assessed by the severity of alopecia tool (SALT), duration of hair growth after completion of therapy, and disease transcriptome.

RESULTS. Of 66 subjects treated, 32% experienced 50% or greater improvement in SALT score. AA and ophiasis subtypes were more responsive than AT and AU subtypes. Shorter duration of disease and histological peribulbar inflammation on pretreatment scalp biopsies were associated with improvement in SALT score. Drug cessation resulted in disease relapse in 8.5 weeks. Adverse events were limited to grade I and II infections. An AA responsiveness to JAK/STAT inhibitors score was developed to segregate responders and nonresponders, and the previously developed AA disease activity index score tracked response to treatment.

CONCLUSIONS. At the dose and duration studied, tofacitinib is a safe and effective treatment for severe AA, though it does not result in a durable response. Transcriptome changes reveal unexpected molecular complexity within the disease.

TRIAL REGISTRATION. ClinicalTrials.gov NCT02197455 and NCT02312882.

FUNDING. This work was supported by the US Department of Veterans Affairs Office of Research and Development, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health grant R01 AR47223 and U01 AR67173, the National Psoriasis Foundation, the Swedish Society of Medicine, the Fernström Foundation, the Locks of Love Foundation, the National Alopecia Areata Foundation, and the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research.

Authors

Milène Kennedy Crispin, Justin M. Ko, Brittany G. Craiglow, Shufeng Li, Gautam Shankar, Jennifer R. Urban, James C. Chen, Jane E. Cerise, Ali Jabbari, Mårten C.G. Winge, M. Peter Marinkovich, Angela M. Christiano, Anthony E. Oro, Brett A. King

Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata

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Abstract

BACKGROUND. Alopecia areata (AA) is a common autoimmune disease with a lifetime risk of 1.7%; there are no FDA-approved treatments for AA. We previously identified a dominant IFN-γ transcriptional signature in cytotoxic T lymphocytes (CTLs) in human and mouse AA skin and showed that treatment with JAK inhibitors induced durable hair regrowth in mice by targeting this pathway. Here, we investigated the use of the oral JAK1/2 inhibitor ruxolitinib in the treatment of patients with moderate-to-severe AA.

METHODS. We initiated an open-label clinical trial of 12 patients with moderate-to-severe AA, using oral ruxolitinib, 20 mg twice per day, for 3–6 months of treatment followed by 3 months follow-up off drug. The primary endpoint was the proportion of subjects with 50% or greater hair regrowth from baseline to end of treatment.

RESULTS. Nine of twelve patients (75%) demonstrated a remarkable response to treatment, with average hair regrowth of 92% at the end of treatment. Safety parameters remained largely within normal limits, and no serious adverse effects were reported. Gene expression profiling revealed treatment-related downregulation of inflammatory markers, including signatures for CTLs and IFN response genes and upregulation of hair-specific markers.

CONCLUSION. In this pilot study, 9 of 12 patients (75%) treated with ruxolitinib showed significant scalp hair regrowth and improvement of AA. Larger randomized controlled trials are needed to further assess the safety and efficacy of ruxolitinib in the treatment of AA.

TRIAL REGISTRATION. Clinicaltrials.gov NCT01950780.

FUNDING. Locks of Love Foundation, the Alopecia Areata Initiative, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the Irving Institute for Clinical and Translational Research/Columbia University Medical Center Clinical and Translational Science Award (CUMC CTSA).

Authors

Julian Mackay-Wiggan, Ali Jabbari, Nhan Nguyen, Jane E. Cerise, Charlotte Clark, Grace Ulerio, Megan Furniss, Roger Vaughan, Angela M. Christiano, Raphael Clynes

Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia

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Abstract

Levodopa-induced dyskinesia (LID) is the most common, disruptive complication of Parkinson’s disease (PD) pharmacotherapy, yet despite decades of research, the changes in regional brain function underlying LID remain largely unknown. We previously found that the cerebral vasomotor and metabolic responses to levodopa are dissociated in PD subjects. Nonetheless, it is unclear whether levodopa-mediated dissociation is exaggerated in LID or distinguishes LID from non-LID subjects. To explore this possibility, we used dual-tracer positron emission tomography to quantify regional cerebral blood flow and metabolic activity in 28 PD subjects (14 LID, 14 non-LID), scanned before and during intravenous levodopa infusion. Levodopa-mediated dissociation was most prominent in the posterior putamen (P < 0.0001) and greater in LID than in non-LID and test-retest subjects. Strikingly, LID subjects also showed increased sensorimotor cortex (SMC) activity in the baseline, unmedicated state. Imaging data from an independent PD sample (106 subjects) linked these differences to loss of mesocortical dopamine terminals in advanced patients. In aggregate, the data suggest that LID results from an overactive vasomotor response to levodopa in the putamen on a background of disease-related increases in SMC activity. LID may thus be amenable to treatment that modulates the function of these 2 regions.

Authors

Vincent A. Jourdain, Chris C. Tang, Florian Holtbernd, Christian Dresel, Yoon Young Choi, Yilong Ma, Vijay Dhawan, David Eidelberg

Multiparametric profiling of non–small-cell lung cancers reveals distinct immunophenotypes

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Abstract

BACKGROUND. Immune checkpoint blockade improves survival in a subset of patients with non–small-cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited.

METHODS. We performed comprehensive flow cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next-generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC).

RESULTS. Cytometric profiling identified an immunologically “hot” cluster with abundant CD8⁺ T cells expressing high levels of PD-1 and TIM-3 and an immunologically “cold” cluster with lower relative abundance of CD8⁺ T cells and expression of inhibitory markers. The “hot” cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the “hot” cluster. Additionally, approximately 20% of cases had high B cell infiltrates with a subset producing IL-10.

CONCLUSIONS. Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer.

FUNDING. The Robert A. and Renée E. Belfer Family Foundation, Expect Miracles Foundation, Starr Cancer Consortium, Stand Up to Cancer Foundation, Conquer Cancer Foundation, International Association for the Study of Lung Cancer, National Cancer Institute (R01 CA205150), and the Damon Runyon Cancer Research Foundation.

Authors

Patrick H. Lizotte, Elena V. Ivanova, Mark M. Awad, Robert E. Jones, Lauren Keogh, Hongye Liu, Ruben Dries, Christina Almonte, Grit S. Herter-Sprie, Abigail Santos, Nora B. Feeney, Cloud P. Paweletz, Meghana M. Kulkarni, Adam J. Bass, Anil K. Rustgi, Guo-Cheng Yuan, Donald W. Kufe, Pasi A. Jänne, Peter S. Hammerman, Lynette M. Sholl, F. Stephen Hodi, William G. Richards, Raphael Bueno, Jessie M. English, Mark A. Bittinger, Kwok-Kin Wong

Increased mitochondrial DNA deletions and copy number in transfusion-dependent thalassemia

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Abstract

BACKGROUND. Iron overload is the primary cause of morbidity in transfusion-dependent thalassemia. Increase in iron causes mitochondrial dysfunction under experimental conditions, but the occurrence and significance of mitochondrial damage is not understood in patients with thalassemia.

METHODS. Mitochondrial DNA (mtDNA) to nuclear DNA copy number (Mt/N) and frequency of the common 4977-bp mitochondrial deletion (ΔmtDNA⁴⁹⁷⁷) were quantified using a quantitative PCR assay on whole blood samples from 38 subjects with thalassemia who were receiving regular transfusions.

RESULTS. Compared with healthy controls, Mt/N and ΔmtDNA⁴⁹⁷⁷ frequency were elevated in thalassemia (P = 0.038 and P < 0.001, respectively). ΔmtDNA⁴⁹⁷⁷ was increased in the presence of either liver iron concentration > 15 mg/g dry-weight or splenectomy, with the highest levels observed in subjects who had both risk factors (P = 0.003). Myocardial iron (MRI T2* < 20 ms) was present in 0%, 22%, and 46% of subjects with ΔmtDNA⁴⁹⁷⁷ frequency < 20, 20–40, and > 40/1 × 10⁷ mtDNA, respectively (P = 0.025). Subjects with Mt/N values below the group median had significantly lower Matsuda insulin sensitivity index (5.76 ± 0.53) compared with the high Mt/N group (9.11 ± 0.95, P = 0.008).

CONCLUSION. Individuals with transfusion-dependent thalassemia demonstrate age-related increase in mtDNA damage in leukocytes. These changes are markedly amplified by splenectomy and are associated with extrahepatic iron deposition. Elevated mtDNA damage in blood cells may predict the risk of iron-associated organ damage in thalassemia.

FUNDING. This project was supported by Children’s Hospital & Research Center Oakland Institutional Research Award and by the National Center for Advancing Translational Sciences, NIH, through UCSF-CTSI grant UL1 TR000004.

Authors

Ashutosh Lal, Esteban Gomez, Cassandra Calloway

Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses

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Abstract

BACKGROUND. Enzyme replacement therapy (ERT) has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD), a rapidly progressive neuromuscular disorder. Yet marked interindividual variability in response to ERT, primarily attributable to the development of antibodies to ERT, remains an ongoing challenge. Immune tolerance to ongoing ERT has yet to be described in the setting of an entrenched immune response.

METHODS. Three infantile Pompe patients who developed high and sustained rhGAA IgG antibody titers (HSAT) and received a bortezomib-based immune tolerance induction (ITI) regimen were included in the study and were followed longitudinally to monitor the long-term safety and efficacy. A trial to taper the ITI protocol was attempted to monitor if true immune tolerance was achieved.

RESULTS. Bortezomib-based ITI protocol was safely tolerated and led to a significant decline in rhGAA antibody titers with concomitant sustained clinical improvement. Two of the 3 IPD patients were successfully weaned off all ITI protocol medications and continue to maintain low/no antibody titers. ITI protocol was significantly tapered in the third IPD patient. B cell recovery was observed in all 3 IPD patients.

CONCLUSION. This is the first report to our knowledge on successful induction of long-term immune tolerance in patients with IPD and HSAT refractory to agents such as cyclophosphamide, rituximab, and methotrexate, based on an approach using the proteasome inhibitor bortezomib. As immune responses limit the efficacy and cost-effectiveness of therapy for many conditions, proteasome inhibitors may have new therapeutic applications.

FUNDING. This research was supported by a grant from the Genzyme Corporation, a Sanofi Company (Cambridge, Massachusetts, USA), and in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network (RDCRN).

Authors

Zoheb B. Kazi, Sean N. Prater, Joyce A. Kobori, David Viskochil, Carrie Bailey, Renuka Gera, David W. Stockton, Paul McIntosh, Amy S. Rosenberg, Priya S. Kishnani

PD-1⁺ and Foxp3⁺ T cell reduction correlates with survival of HCC patients after sorafenib therapy

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Abstract

BACKGROUND. Sorafenib is an oral antiangiogenic agent administered in advanced-stage hepatocellular carcinoma (HCC). Based on preclinical and human studies, we hypothesized that, in addition to its antiangiogenic properties, sorafenib may beneficially reduce the extent of the immunosuppressive network in HCC patients. To test this hypothesis, we examined whether alterations in the immunosuppressive burden of advanced-stage HCC patients correlated with clinical outcome.

METHODS. In before and after sorafenib treatment, blood samples collected from 19 patients with advanced HCC, the frequency of PD-1⁺ T cells, Tregs, and myeloid derived suppressor cells (MDSC) were quantified by multiparameter FACS. Cytokine levels in plasma were determined by ELISA.

RESULTS. Overall survival (OS) was significantly impacted by the reduction in the absolute number of both CD4⁺PD-1⁺ T cells and CD8⁺PD-1⁺ T cells following sorafenib treatment. Significant decreases in the frequency and absolute number of Foxp3⁺ Tregs were also observed, and a statistically significant improvement in OS was noted in patients exhibiting a greater decrease in the number of Foxp3⁺ Tregs. The ratio of CD4⁺CD127⁺PD-1^– T effector cells to CD4⁺Foxp3⁺PD-1⁺ Tregs was significantly increased following treatment with sorafenib. Increased frequency of CD4⁺CD127⁺ T effector cells in the posttreatment samples significantly correlated with OS.

CONCLUSION. This study is the first to our knowledge to demonstrate the potent immunomodulatory effects of sorafenib therapy on PD-1⁺ T cells and Tregs and the ensuing correlation with survival. These phenotypes could serve as predictive biomarkers to identify HCC patients who are likely to benefit from sorafenib treatment.

TRIAL REGISTRATION. Registration is not required for observational studies.

FUNDING. This study was supported by NCI Core Grant to RPCI (NIH P30 CA016056) and discretionary funds to Y. Thanavala.

Authors

Suresh Gopi Kalathil, Amit Anand Lugade, Austin Miller, Renuka Iyer, Yasmin Thanavala

Soluble membrane attack complex is diagnostic for intraventricular shunt infection in children

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Abstract

BACKGROUND. Children treated with cerebrospinal fluid (CSF) shunts to manage hydrocephalus frequently develop shunt failure and/or infections, conditions that present with overlapping symptoms. The potential life-threatening nature of shunt infections requires rapid diagnosis; however, traditional microbiology is time consuming, expensive, and potentially unreliable. We set out to identify a biomarker that would identify shunt infection.

METHODS. CSF was assayed for the soluble membrane attack complex (sMAC) by ELISA in patients with suspected shunt failure or infection. CSF was obtained at the time of initial surgical intervention. Statistical analysis was performed to assess the diagnostic potential of sMAC in pyogenic-infected versus noninfected patients.

RESULTS. Children with pyogenic shunt infection had significantly increased sMAC levels compared with noninfected patients (3,211 ± 1,111 ng/ml vs. 26 ± 3.8 ng/ml, P = 0.0001). In infected patients undergoing serial CSF draws, sMAC levels were prognostic for both positive and negative clinical outcomes. Children with delayed, broth-only growth of commensal organisms (P. acnes, S. epidermidis, etc.) had the lowest sMAC levels (7.96 ± 1.7 ng/ml), suggesting contamination rather than shunt infection.

CONCLUSION. Elevated CSF sMAC levels are both sensitive and specific for diagnosing pyogenic shunt infection and may serve as a useful prognostic biomarker during recovery from infection.

FUNDING. This work was supported in part by the Impact Fund of Children’s of Alabama.

Authors

Theresa N. Ramos, Anastasia A. Arynchyna, Tessa E. Blackburn, Scott R. Barnum, James M. Johnston

Asfotase alfa therapy for children with hypophosphatasia

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Abstract

Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP.

Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6–12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients.

Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti–asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance.

Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP.

Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826).

Funding. Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children.

Authors

Michael P. Whyte, Katherine L. Madson, Dawn Phillips, Amy L. Reeves, William H. McAlister, Amy Yakimoski, Karen E. Mack, Kim Hamilton, Kori Kagan, Kenji P. Fujita, David D. Thompson, Scott Moseley, Tatjana Odrljin, Cheryl Rockman-Greenberg

A clinical measure of DNA methylation predicts outcome in de novo acute myeloid leukemia

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Abstract

BACKGROUND. Variable response to chemotherapy in acute myeloid leukemia (AML) represents a major treatment challenge. Clinical and genetic features incompletely predict outcome. The value of clinical epigenetic assays for risk classification has not been extensively explored. We assess the prognostic implications of a clinical assay for multilocus DNA methylation on adult patients with de novo AML.

METHODS. We performed multilocus DNA methylation assessment using xMELP on samples and calculated a methylation statistic (M-score) for 166 patients from UPENN with de novo AML who received induction chemotherapy. The association of M-score with complete remission (CR) and overall survival (OS) was evaluated. The optimal M-score cut-point for identifying groups with differing survival was used to define a binary M-score classifier. This classifier was validated in an independent cohort of 383 patients from the Eastern Cooperative Oncology Group Trial 1900 (E1900; NCT00049517).

RESULTS. A higher mean M-score was associated with death and failure to achieve CR. Multivariable analysis confirmed that a higher M-score was associated with death (P = 0.011) and failure to achieve CR (P = 0.034). Median survival was 26.6 months versus 10.6 months for low and high M-score groups. The ability of the M-score to perform as a classifier was confirmed in patients ≤ 60 years with intermediate cytogenetics and patients who achieved CR, as well as in the E1900 validation cohort.

CONCLUSION. The M-score represents a valid binary prognostic classifier for patients with de novo AML. The xMELP assay and associated M-score can be used for prognosis and should be further investigated for clinical decision making in AML patients.

Authors

Marlise R. Luskin, Phyllis A. Gimotty, Catherine Smith, Alison W. Loren, Maria E. Figueroa, Jenna Harrison, Zhuoxin Sun, Martin S. Tallman, Elisabeth M. Paietta, Mark R. Litzow, Ari M. Melnick, Ross L. Levine, Hugo F. Fernandez, Selina M. Luger, Martin Carroll, Stephen R. Master, Gerald B.W. Wertheim