Blood Advances in a Different Vein
in change in certain echocardiographic parameters among patients taking hydroxyurea ,” the researchers concluded that the study indicates that the use of disease-modifying therapies such as hydroxyurea “ may limit the progression of , and potentially improve , cardiac abnormalities over time .”
The study was a single-center retrospective study , further limiting the findings . “ It would be good to see a prospective multicenter study that follows these patients for a longer period of time , and even into adulthood , when cardiac complications become even more common ,” commented Dr . Dhar .
Study authors report no relevant conflicts of interest .
Reference Dhar A , Leung TM , Appiah-Kubi A , et al . Longitudinal analysis of cardiac abnormalities in pediatric patients with sickle cell anemia and effect of hydroxyurea therapy [ published online ahead of print , 2021 Sep 16 ]. Blood Adv . doi : 10.1182 / bloodadvances . 2021005076 .
Idiopathic Multicentric Castleman Disease : Identifying Prevalence and New Treatment Targets
Two recent studies published in Blood Advances explored idiopathic multicentric Castleman disease ( iMCD ). Researchers led by Sudipto Mukherjee , MD , MPH , of Cleveland Clinic , provided an updated understanding of the epidemiology of iMCD and identified an unmet need for interleukin-6 ( IL-6 ) directed therapy for patients with iMCD in the U . S . Another study , led by Sheila K . Pierson , MS , of the University of Pennsylvania , examined the responses of patients with iMCD to anti-IL-6 therapy siltuximab and discovered a new therapeutic pathway for patients with iMCD who did not respond to siltuximab .
Prevalence of iMCD in the U . S .
To estimate the total number of iMCD cases in the U . S ., Dr . Mukherjee and colleagues applied a claims-based algorithm to a base sample population of 30.7 million insured healthy individuals and patients with medical conditions . This algorithm included a Castleman disease – specific ICD-10 diagnosis code ( D47 . Z2 ) and relied on the presence of ≥2 codes corresponding to minor international evidence-based diagnostic criteria for iMCD . The investigators sourced deidentified longitudinal patient data from the IBM MarketScan Research Databases of inpatient and outpatient claims from January 2006 through March 2020 .
Prior to this study , limited data was available on the epidemiology and treatment of iMCD – and Castleman disease more broadly – because of nonspecific diagnostic coding , according to Dr . Mukherjee .
In the U . S ., the annual incidence and prevalence of iMCD was estimated at 3.4 cases per million ( 95 % CI 1.4-9.2 ) and 6.9 cases per million ( 95 % CI 3.7-13.3 ), respectively . According to the authors ’ estimates , approximately 2,246 patients with iMCD ( 95 % CI 1,223-4,348 ) were alive in the U . S . in 2017 and 3,172 in 2018 ( 95 % CI 1,820-5,835 ).
Unmet Treatment Needs
Dr . Mukherjee and colleagues also performed a treatment pattern analysis and found that only 9.8 % of patients with iMCD received an IL-6 – targeted therapy , while 33.1 % received no treatment , and 39 % received corticosteroid monotherapy . “ Given that siltuximab is the only FDA- and EMA-approved treatment for iMCD based on randomized controlled trial data and considering the morbidity and mortality associated with this condition , it is surprising that 90.2 % of iMCD patients did not receive IL-6 targeted therapies ,” Dr . Mukherjee wrote .
“ Our findings highlight significant treatment gaps for iMCD patients , a large unmet treatment need for IL-6 – directed therapies , and poor adherence to treatment guidelines ,” he wrote .
Response to Siltuximab and New Treatment Pathways
Using a hierarchical clustering algorithm , Ms . Pierson and colleagues characterized the serum proteome of iMCD in the context of clinicopathologically overlapping diseases Hodgkin lymphoma ( HL ), rheumatoid arthritis ( RA ), and human herpesvirus 8 ( HHV8 ) -associated MCD . The researchers obtained samples from 73 patients with iMCD from a randomized phase II study of siltuximab and samples from 15 patients from real-world practice at six clinical sites . 3 For comparison , they also obtained samples from 60
“ Our findings highlight significant treatment gaps for iMCD patients , a large unmet treatment need for IL-6 directed therapies , and poor adherence to treatment guidelines .”
— Sudipto Mukherjee , MD , MPH
patients with HHV8-associated MCD ( n = 20 ), HL ( n = 20 ), and RA ( n = 20 ), as well as 42 healthy individuals . A validation cohort comprised 23 patients with iMCD who were enrolled in a phase I study of siltuximab . 4
Among patients with iMCD whose disease did not respond to siltuximab , significant signaling of IL-6-JAK-STAT3 was observed in the enrichment analysis , despite the fact that IL-6 inhibition is ineffective in this subgroup . One-quarter of patients with iMCD in the study clustered with HL . In HL , increased IL-6 and IL-6 receptor expression are associated with worse survival outcomes , JAK-mediated signaling , sensitivity to the JAK1 / 2 inhibitor ruxolitinib , and increased pSTAT3 expression . Additionally , the researchers found that the peripheral blood mononuclear cells of patients in remission from iMCD demonstrated hypersensitivity to IL-6 simulation in vitro . “ Together , these data suggest dysregulation of the IL-6-JAK-STAT3 signaling pathway may be important in iMCD ,” Ms . Pierson wrote .
For patients with iMCD who do not respond to siltuximab , targeting the IL-6-JAK-STAT3 pathway with ruxolitinib , which has demonstrated activity in other hyperinflammatory , cytokinedriven diseases , may be useful , according to the investigators . Through their enrichment analysis , Ms . Pierson and colleagues identified additional pathways contributing to disease process in patients with iMCD that can be targeted with FDA-approved agents , including TNF alpha , interferon gamma , IL-2 , and components of the allograft rejection signature . Considering their clinical activity in autoimmune diseases like RA and the proteomic overlap between some patients with iMCD and RA , “ anti-TNF alpha drugs should be further investigated ,” the authors wrote . ●
Study authors report no relevant conflicts of interest .
References
1 . Pierson SK , Shenoy S , Oromendia AB , et al . Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease . Blood Adv . 2021 ; 5 ( 17 ): 3445-3456 .
2 . Mukherjee S , Martin R , Sande B , et al . Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6 directed therapy [ published online ahead of print , 2021 Sep 17 ]. Blood Adv . doi : 10.1182 / bloodadvances . 2021004441 .
3 . van Rhee F , Wong RS , Munshi N , et al . Siltuximab for multicentric Castleman ’ s disease : a randomised , double-blind , placebo-controlled trial . Lancet Oncol . 2014 ; 15 ( 9 ): 966-974 .
4 . Kurzrock R , Voorhees PM , Casper C , et al . A phase I , open-label study of siltuximab , an anti-IL-6 monoclonal antibody , in patients with B-cell non- Hodgkin lymphoma , multiple myeloma , or Castleman disease . Clin Cancer Res . 2013 ; 19:3659-3670 .
20 ASH Clinical News Bonus 2021 ASH Annual Meeting Preview Edition