With more than 18,000 members from nearly 100 countries, the American Society of Hematology (ASH) is the world’s largest professional society serving both clinicians and scientists around the world who are working to conquer blood diseases.
The CDCN’s work on Castleman disease was submitted to the annual conference. Read more below on each abstract.
UCD experience
Unicentric Castleman disease (UCD) is the most common subtype of Castleman disease and complete excision of the enlarged lymph node has been thought to be curative. However, many UCD patients have told us that they have persistence or worsening of symptoms after lymph node excision despite having normal laboratory values and absence of measurably enlarged lymph nodes. Many patients also prioritized this as part of AIM2021 so we decided to focus efforts on this. We sent a survey to all UCD patients in the ACCELERATE (www.CDCN.org/ACCELERATE) Castleman disease registry and 51 UCD patients responded. Surprisingly, 57% of patients reported having continued symptoms after lymph node excision. Common ongoing symptoms included fatigue (61%) and night sweats (39%). These data indicate—for the first time ever–that complete lymph node excision may not result in a cure or symptom-free outcomes for UCD patients. This has driven the CDCN to continue to support research into UCD to identify new treatments for patients with unresectable UCD and patients with post-resection symptoms. Check out early results from this study here!
COVID experience
In the most severe cases of Castleman disease (CD), patients experience a cytokine storm — a life-threatening exacerbation of circulating cytokines and immune cell hyperactivation. Similarly, SARS-CoV-2 elicits a severe cytokine storm in the most severe cases of COVID-19. One cytokine, interleukin-6 (IL-6) is thought to be central to the pathogenesis of CD and has been shown to be increased in severe COVID-19 cases. Furthermore, blocking IL-6 has been shown to be effective therapy for both CD and severe COVID-19. Given these similarities, our team sought to understand the CD patient experience with vaccines and/or infection with SARS-CoV-2 via a survey sent to all CD patients in the ACCELERATE (www.CDCN.org/ACCELERATE) Castleman disease registry, and 101 CD patients responded. Survey results demonstrated that CD patients do not seem to have a higher rate of infection with SARS-CoV-2 than the general US population and COVID-19 infections seem to be of a similar severity in CD patients as the general US population. Furthermore, a large proportion of CD patients have been vaccinated and it was well-tolerated with adverse effects comparable to the general US population. Check out early results from this study here!
Blood smear data
Idiopathic multicentric Castleman disease (iMCD) is a severe subtype of Castleman disease characterized by enlarged lymph nodes in multiple regions in the body, inflammatory symptoms, and life-threatening organ dysfunction. iMCD also has multiple subclassifications whose diagnoses remain challenging given the non-specific nature of their clinical symptoms. Something that could help in the diagnostic journey for iMCD patients is the use of minimally invasive procedures, such as peripheral blood smears. Using data from the ACCELERATE (www.CDCN.org/ACCELERATE) Castleman disease registry, we evaluated the characteristics of blood cells in iMCD patients for the first time ever. Results showed that the red blood cells of iMCD patients had abnormalities in size and color and that enlarged platelets may be a diagnostic clue for iMCD. These findings could aide in the diagnosis and treatment of iMCD patients. Check out early results from this study here!
Mortality data
Idiopathic multicentric Castleman disease (iMCD) is a severe subtype of Castleman disease characterized by enlarged lymph nodes in multiple regions in the body, inflammatory symptoms, and life-threatening organ dysfunction. The estimated five-year overall survival rate varies considerably, ranging from 50-77%. Using our natural history registry, ACCELERATE (www.CDCN.org/ACCELERATE), we were able to compare fatal and non-fatal outcomes in iMCD to identify laboratory features that may be clues that patients are at increased risk of death. We found that low IgM and platelet counts around the time of diagnosis were found more often in patients who died from their disease compared to those who go on to survive. These abnormal lab tests may indicate immune dysregulation or an increased risk of bleeding events. More research is needed into these cases so we can improve treatments and prevent CD patients from dying. Check out early results from this study here!
Spectrum
Castleman disease (CD) describes a group of lymphoproliferative disorders that all look the same under the microscope but differ in terms of number of enlarged lymph nodes, what causes them, and symptoms. Historically, CD has been divided into Unicentric CD (UCD), which involves a single enlarged lymph node station and mild symptoms, and multicentric CD (MCD), which involves multiple (>1) stations of enlarged lymph nodes and more severe symptoms. MCD can be caused by HHV-8 infection (HHV8-associated MCD), POEMS syndrome (POEMS-associated MCD), or for an unknown cause (idiopathic MCD, iMCD).
Recently it has been reported that some patients can have a few enlarged lymph nodes and have symptoms that are more common with UCD. Based on investigation of all CD cases, it emerged that patients who have a single region of enlarged lymph nodes should be classified as UCD, patients with multiple enlarged lymph nodes only above the diaphragm or only below the diaphragm may be more accurately classified as “oligocentric CD,” and patients who have enlarged lymph nodes both above and below the diaphragm should be considered iMCD. Results of this study showed that patients with “oligocentric” lymph nodes above or below the diaphragm appeared to behave more like unicentric Castleman disease (UCD) patients than iMCD patients. Further work is needed to understand how this finding may impact treatment. Check out early results from this study here!
Cytokine levels
Idiopathic multicentric Castleman disease (iMCD) is a severe subtype of Castleman disease characterized by enlarged lymph nodes in multiple regions in the body, inflammatory symptoms, and life-threatening organ dysfunction. One particular cytokine called Interleukin-6 (IL-6) is known to drive the disease in a large portion of patients and siltuximab, which blocks IL-6, is the only FDA-approved treatment for iMCD and is effective in one-third to one-half of patients. However, IL-6 is not consistently elevated and the role of other cytokines in iMCD is not well understood. We measured 1300 molecules in the blood of 88 iMCD patients, 42 healthy individuals, and 20 patients each with rheumatoid arthritis (RA), Hodgkin lymphoma (HL), and HHV-8-associated multicentric Castleman disease. We discovered that CXCL13 was the most elevated cytokine in iMCD compared to healthy individuals. IL-6 was ranked 31 out of 54 cytokines. Further research into CXCL13 and the cell types that produce CXCL13 called lymph node stromal cells is underway. Studies of CXCL13 blockers may be warranted in the future for iMCD patients that do not benefit from siltuximab.
https://ash.confex.com/ash/2021/webprogram/Paper153893.html
IL6 modeling
Idiopathic multicentric Castleman disease (iMCD) is a severe subtype of Castleman disease characterized by enlarged lymph nodes in multiple regions in the body, inflammatory symptoms, and life-threatening organ dysfunction. One particular cytokine called Interleukin-6 (IL-6) is known to drive the disease in a large portion of patients and siltuximab, which blocks IL-6, is the only FDA-approved treatment for iMCD and is effective in one-third to one-half of patients. Among the one-half to two-thirds of iMCD patients that do not respond to siltuximab, it is unclear the best way to treat them. The CDCN has discovered mTOR inhibitors such as sirolimus and JAK inhibitors such as ruxolitinib as possible treatment approaches for these patients but additional treatment approaches are needed. A research team in France led a mathematical study to model the ability of siltuximab and tocilizumab to inhibit IL-6 activity from data on C-reactive protein levels after treatment administration. The researchers found that some iMCD patients who do not respond to siltuximab may be failing to respond because IL-6 levels are not being completely blocked throughout the body and the addition of tocilizumab could be helpful for these patients. More research is needed but this is an exciting idea.