Hello, my name is Doctor Sujit Sheth, and I am the Chief of the Division of Pediatric Hematology/Oncology at Weill Cornell Medicine and an attending pediatrician at New York Presbyterian Hospital, in New York City.

Along with my co-authors, it’s my pleasure to introduce you to our recently published work in Blood Advances titled “Rates of severe neutropenia and infection risk in patients treated with deferiprone: 28 years of data”.

Idiosyncratic drug-induced neutropenia or IDIN can occur with the use of many medications. Patients who develop severe IDIN have an absolute neutrophil count, or ANC, of less than 500/µL. Throughout the video, I will refer to severe IDIN as severe neutropenia.
With the decline in neutrophils, these individuals are at risk of serious and sometimes fatal infections.

Deferiprone is an oral iron chelator indicated for transfusional iron overload in adult and pediatric patients with thalassemia, sickle cell disease, or other anemias. Treatment with deferiprone is associated with transient episodes of neutropenia of variable severity and predictability.
Prior to this study, the risk of infection in patients who experience deferiprone-associated severe neutropenia, was not well studied. Our aim was to determine the risk of serious infection associated with severe neutropenia, stratified by ANC levels in patients taking deferiprone.
In this analysis, we used a large data set and extracted events of severe neutropenia and then we identified risk of serious infections that occurred within 2 weeks of those events. We used two data sets: company sponsored trials of deferiprone and the postmarketing surveillance program.
Newly published guidelines by the EHA/INNOCHRON suggest that severe chronic neutropenias with ANC below 200/µL may be termed ‘agranulocytosis’ and they are associated with a high risk of severe, life-threatening infections.

Therefore, in our analysis, we looked at serious infections associated with severe neutropenia within 3 discrete ANC groups. Group 1 with ANC between 200 and 500/µL; Group 2 with ANC between 100 and 199, and Group 3 with ANC less than 100.

In 15 company sponsored trials, we identified a total of 22 events of severe neutropenia. 9 events were within Group 1, 3 events were within Group 2, and 10 events were within Group 3. Interestingly, none of the events of severe neutropenia in Groups 1 and 2 were associated with serious infections. Of the 10 events in Group 3, 3 were associated with serious infections. There was also 1 death in Group 3.

The death was due to hospital acquired pneumonia and multisystem organ failure following Pseudomonas sepsis associated with deferiprone-induced severe neutropenia.
From the postmarketing surveillance program, a total of 238 events of severe neutropenia were reported by clinicians, patients, or caregivers. Of those, 176 events had at least 1 ANC value reported. These events were then analyzed. Of these 176 events, 65 were in group 1, 20 in group 2 and 91 in group 3. There were 5 serious infections in group 1 or 7.7%, 2 in group 2 or 10%, and 12 in group 3 or 13.2%, showing a trend of increasing risk with lower ANC values. The mortality trend was similar, with 4.6% in group 1, 5% in group 2 and 8.8% in group 3. More details on all of the infectious events in this study can be found in the manuscript.

Based on our findings from 15 company sponsored trials of deferiprone and over 20 years of real-world data, we found that the lowest ANC levels below 200 or below 100 were associated with a higher risk of infections and mortality compared with the ANCs between 200 and 500. This is also consistent with the European guidelines on neutropenia, which I mentioned previously.
In conclusion, our analysis has demonstrated that lower ANC thresholds of 200 or 100 may be more clinically relevant in the deferiprone treatment landscape and may be used to define agranulocytosis, somewhat reassuring both clinicians and patients.

However, a proactive approach to monitoring ANC levels, and detecting early signs of infection is recommended for all patients regardless of the severity of neutropenia.

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Jean Donadieu, MD Service d'Hémato-Oncologie Pédiatrique, Hopital, Paris, provides an overview of WHIM syndrome.

WHIM syndrome is a rare, congenital primary immunodeficiency disorder associated with neutropenia that typically presents in childhood or adolescence. However, due to the heterogeneous presentation of the disease, coupled with lack of awareness of the condition, recognition and diagnosis is often delayed, sometimes even into adulthood. Consequently, WHIM syndrome may be misdiagnosed and underdiagnosed.

To an extent, the name WHIM syndrome is a misnomer. The symptoms listed in the acronym (W)arts, (H)ypogammaglobulinemia, (I)nfections, and (M)yelokathexis do not describe the most common manifestations of the disorder, and only 23% of patients present with all four symptoms comprising WHIM.

In fact, the most common symptoms in patients diagnosed with WHIM syndrome are the laboratory findings of neutropenia (98%) and lymphopenia (88%).[3] Warts were seen in only 42% of one 66-patient cohort (though in more than half in another study), hypogammaglobulinemia in 65%, and recurrent infections in 92%. Myelokathexis, revealed via bone marrow biopsy, is often used to confirm the diagnosis, along with genetic testing.

The initial clinical sign of WHIM syndrome is recurrent infection. In a survey of patients with WHIM syndrome, Geier and colleagues[3] found that recurrent infection was the first recognizable symptom in 88% of patients (most commonly bacterial respiratory infections [49%] or otitis media [23%]). Skin infections were seen initially in 13%, and HPV-related infections (including warts) were the first recognized symptom in only 2% of patients. In this survey, 96% of patients with WHIM syndrome presented their initial symptom by age 5 years; 70% presented by 1 year of age.

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Dr. Sonal Kumar, an Assistant Professor of Medicine, and Director of Clinical Hepatology at Weill Cornell Medical College in New York, NY discusses the integral role of the patient voice in navigating treatment decisions and determining an individualized care plan for people living with primary biliary cholangitis (PBC) that reflects their needs and goals.

©2024 Ipsen Biopharmaceuticals, Inc. All rights reserved.

IQV-US-000526 | July 2024

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João Gonçalves
Faculty of Pharmacy
University of Lisbon
Lisbon, Portugal

Paolo Caliceti
Department of Pharmaceutical and Pharmacological Sciences
University of Padova
Padova, Italy

What Is PEGylation and Why Is It Important?
We will begin by examining the clinical uses of therapeutic proteins, and their applications in healthcare. Next, we will discuss the inherent limitations of therapeutic proteins, including challenges such as pharmacokinetic (PK) profiles, protein aggregation during storage, and potential immune responses. The session will then delve into the process of PEGylation, where polyethylene glycol (PEG) is conjugated to functional amino acid groups on the protein surface. This modification may enhance the properties of therapeutic proteins, offering advantages in stability, half-life, and immunogenicity.

Biopharmaceutical and Immunological Properties of PEGylated Proteins
We will explore the biopharmaceutical and immunological properties of PEGylated proteins, focusing on how their unique structure and composition impact their function. We will discuss how each PEGylated protein has distinct properties based on PEG architecture, molecular weight and degree of conjugation that cannot be generalized across different pegylated molecules, highlighting the variability in pharmacokinetic (PK) characteristics such as half-life, absorption, distribution, and elimination. These factors can significantly influence clinical outcomes, including dosing intervals and overall therapeutic effectiveness. We will also address the potential clinical advantages and limitations of PEGylation, with real-world examples to illustrate how these proteins are used in practice.

Immunogenicity Considerations of PEGylated Proteins
We will explore the immunogenicity of PEGylated proteins, examining both the potential benefits and risks associated with PEG modification. While PEGylation can trigger immune responses against PEG itself or the PEGylated protein, it can also help mask epitopes and reduce anti-drug antibodies formation. Drug- and patient-related factors that influence immunogenicity risk will also be covered, along with the prevalence and impact of pre-existing anti-drug antibodies (ADAs).We will discuss the potential clinical consequences of immune reactions to PEG or PEGylated proteins, and how the risk of such responses can vary depending on the unique properties of each PEGylated protein. The session will also address strategies to mitigate anti-PEG immunogenicity, as well as approaches for monitoring immunogenicity across different stages of drug development—from preclinical studies to post-marketing surveillance. Additionally, we will explore tools that may help predict therapeutic responses to PEGylated proteins, touching on potential areas for future research.

Discussion and Conclusion
By the end of the session, participants will gain a comprehensive understanding of:
How PEGylation represents a major technological advancement in the development and optimization of therapeutic proteins.
How PEGylation affects both the biopharmaceutical properties and clinical applications of therapeutic proteins
Immunogenicity in the context of PEGylated proteins and the strategies used to manage and predict immune responses.
The role of PEGylation in therapeutic outcomes and the future opportunities for innovation in this field.


This educational webinar is based on the presenters’ manuscript titled “Optimizing Pharmacological and Immunological Properties of Therapeutic Proteins Through PEGylation: Investigating Key Parameters and Their Impact”, published in Drug Design, Development and Therapy.

Editorial support for the webinar was provided by Selene Medical Communications and funded by Chiesi Global Rare Diseases. The presenters have been compensated by Chiesi for their time presenting this webinar. All content is disease-state focused, and the presentation will not include information on specific products as treatment for any conditions.

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Dr. Mark J. Buchfuhrer discusses clinical practice guidelines update suggesting against the standard use of dopamine agonists for the treatment of restless legs syndrome (RLS).

RLS, also known as Willis-Ekbom disease, is a nervous system disorder that causes an uncontrollable urge to move your limbs. Because RLS can disrupt your sleep, it’s also classified as a sleep disorder.

The cause of RLS remains unknown. However, there is evidence that RLS may be related to a disruption in the pathways of dopamine, a brain chemical that helps regulate movement. There may also be a genetic component, as primary RLS often runs in families.

Symptoms of RLS can be categorized as sensory or sleep related. Sensory symptoms include pain, the urge to move, and uncomfortable sensations, most often in the legs. These have been described as itching, pulling, gnawing, and the creepy- crawlies. These symptoms often get worse at night. Sleep symptoms include the inability to fall asleep or stay asleep and insufficient sleep. All of these symptoms may result in disturbed sleep, which has a broader impact on your quality of life.

Dr. Buchfuhrer is a paid
consultant of Azurity
Pharmaceuticals, Inc. Azurity
Pharmaceuticals, Inc. is the
sponsor of the video. Azurity
Pharmaceuticals, Inc. does
not claim that the views
contained in this video are
representative of all
experiences or viewpoints on
the subjects discussed.
Individual patient experience s
may vary.

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This educational program is made possible by an unrestricted grant from Takeda Pharmaceuticals.

Participants
Aleena Banerji, MD
Professor of Medicine, Harvard Medical School and Massachusetts General Hospital,
Boston, MA.

Timothy Craig, DO
Tenured Professor of Medicine, Pediatrics, Biomedical Sciences and OB/GYN, Penn State University, Hershey, PA.
Senior Medical Advisor Vinmec International Hospital, Times City, Hanoi, Vietnam

Marc Riedl, MD
Professor of Medicine, University of California, San Diego School of Medicine,
San Diego, CA.

Hereditary angioedema (HAE) is a rare genetic disease that results in immunologic attacks that can be life-threatening. HAE is the result of reduced levels of C1-inhibitor, a protein involved in various physiological processes in plasma, most notably with the complement system. C1-inhibitor also binds and inhibits plasma kallikrein and factor XIa, thereby affecting bradykinin production. It is believed that the disruptions of these processes lead to fluid leaking from the blood to connective tissue which leads to HAE attacks. [1,2] It is these HAE attacks that tend to put persons in the emergency department or unable to attend work or school. [3]

Numerous therapies are now available for patients with HAE to both treat acute attacks and prevent attacks via prophylactic treatment. [4-11].

With so many treatment options now available, is it disheartening to learn that not all patients with HAE are receiving equal care or access to care. Patients with HAE living in rural areas as patients from underrepresented racial or ethnic backgrounds are not provided the same level of care as patients, especially Caucasian patients, living in more affluent areas. [12-16]

This panel discussion by three clinical research leaders in HAE, Drs. Aleena Banerji, Timothy Craig, and Marc Riedl, provide an overview of the discrepancies in care observed in certain patient populations, as well as a discussion on best practices to reduce those inequalities moving forward.

References
1. Smith TD, Riedl MA. The future of therapeutic options for hereditary angioedema. Ann Allergy Asthma Immunol. 2024; doi: 10.1016/j.anai.2024.04.029 [online ahead of print]
2. Grumach AS et al. Current challenges and future opportunities in patient-focused management of hereditary angioedema: a narrative review. Clin Transl Allergy. 2023; 13: e12243.
3. Lumry WR. Hereditary angioedema: The economics of treatment of an orphan disease. Front Med. 2018;5:22.
4. Center Watch. Berinert (C1 Esterase Inhibitor (Human)). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3229-berinert-c1-esterase-inhibitor-human
5. Center Watch. Kalbitor (ecallantide). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3690-kalbitor-ecallantide
6. Center Watch. Firazyr (icatibant). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3534-firazyr-icatibant
7. Center Watch. Ruconest (C1 esterase inhibitor [recombinant]). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4155-ruconest-c1-esterase-inhibitor-recombinant
8. Center Watch. Cinryze (C1 Inhibitor (Human). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3317-cinryze-c1-inhibitor-human
9. Center Watch. Haegarda (C1 Esterase Inhibitor Subcutaneous [Human]). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/3595-haegarda-c1-esterase-inhibitor-subcutaneous-human
10. Center Watch. Orladeyo (berotralstat). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4666-orladeyo-berotralstat
11. Center Watch. Takhzyro (lanadelumab-flyo). Accessed Jan 21, 2025. https://www.centerwatch.com/directories/1067-fda-approved-drugs/listing/4252-takhzyro-lanadelumab-flyo
12. Riedl MA et al. Optimization of care for patients with hereditary angioedema living in rural areas. Ann Allergy Asthma Immunol. 2022; 128: 526-533.
13. Meadow JA et al. Challenges in the management of hereditary angioedema in urban and rural settings: results of a United States survey. Ann Allergy Asthma Immunol. 2023; 130: 760-767.
14. Brouwer ES et al. Leveraging unstructured data to identify hereditary angioedema patients in electronic medical records. Allergy Asthma Clin Immunol. 2021; 17: 41.
15. Sylvestre S et al. Racial and ethnic disparities in the research and care of hereditary angioedema patients in the United States. J Allergy Clin Immunol Pract. 2021; 9: 4441-4449.
16. Craig TJ et al. Effectiveness and safety of lanadelumab in ethnic and racial minority subgroups of patients with hereditary angioedema: results from phase 3 studies. Allergy Asthma Clin Immunol. 2022; 18:845.

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Yuliya Linhares, MD is a medical oncologist specializing in the comprehensive treatment of lymphoma and serves as chief of Lymphoma Services at Miami Cancer Institute. In this video, Dr. Linhares provides an overview of cutaneous T-cell lymphoma (CTCL) and discusses some strategies for shortening the diagnostic journey of this rare cancer.

The diagnosis of CTCL is often challenging; as a result, delays in diagnosis (and subsequently work-up and treatment) can be significant. Part of the reason is the variability in how individual patients present with CTCL and its subtypes. Because mycosis fungoides progresses slowly, some patients may not experience progression beyond their initial symptoms, even beyond 10 years. Patients with mycosis fungoides or Sézary syndrome also have overlap in manifestations; in fact, Sézary syndrome was once classified as a malignant, leukemic variant of mycosis fungoides but is now recognized as a distinct CTCL subtype.

Patients with mycosis fungoides may progress through three phases of skin symptoms. The first may feature little more than transient red, scaly areas of skin on the buttocks and torso. The plaques may be hyper- or hypopigmented. As such, these symptoms can be easily misidentified as common skin conditions such as eczema or psoriasis. The variability of signs and symptoms also adds to the challenge of making a timely, clear-cut diagnosis.

In the second phase, patients with progressing disease may develop palpable, scaly, reddish-brown plaques that appear on any portion of the body. Over time, the affected areas of skin may grow, merging with other affected regions. Patients’ skin presentation during this stage can vary considerably: Some patients may experience severe pruritus or pain in these scaly bumps, which can result in sleep disturbances and other challenges to quality of life. Other patients may remain asymptomatic other than the skin’s appearance.

Disease presentation is a bit more consistent in patients who have progressed to the third phase of skin symptoms. Some patients may develop mushroom-shaped skin tumors that can cause skin ulceration and infection. Even for patients with mycosis fungoides reaching this phase of skin progression, malignant spread is uncommon (only 10% will experience metastases to major organs).

While patients with Stage III mycosis fungoides experience widespread erythema (over 80% of body surface area), erythroderma is a consistent feature of Sézary syndrome. This rash will often be associated with severe pruritus and peeling.

In addition to erythroderma and B2 blood involvement, patients with Sézary syndrome will typically have several other characteristic signs: generalized lymphadenopathy, opportunistic infections, and alopecia. The liver and possibly the spleen will be enlarged, and patients often have very thick, coarse skin on the soles of the feet and palms of the hands (i.e., palmoplantar keratoderma).

Diagnosis is usually made with a patient history, complete physical exam, blood tests, biopsy of skin lesions, computed tomography imaging, and sometimes lymph node biopsy and/or bone marrow biopsy. These methods can also be useful in determining the stage of disease, especially whether the lymph nodes have been involved and whether the cancerous cells have spread to blood and other organs. In addition to eczema and psoriasis, the differential diagnosis may include nonspecific dermatitis, lichen, lupus, pseudolymphoma, parapsoriasis, and toxidermia.

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Larisa Geskin, MD, Professor of Dermatology at Columbia University Medical Center and Director of the Comprehensive Skin Cancer Center at the Division of Cutaneous Oncology in the Department of Dermatology, discusses the the role of dermatologists in diagnosing and caring for cutaneous T-cell lymphoma (CTCL) patients.

Cutaneous T-cell lymphoma belongs to the non-Hodgkin lymphoma class of hematologic T-cell lymphoproliferative disorders. Cutaneous T-cell lymphoma is a rare group of malignancies, with an incidence of 6.4 cases per 1 million people. This form of T-cell lymphoma represents around 70% of primary cutaneous lymphomas.

Cutaneous T-cell lymphoma attacks the the body’s immune system, specifically, the lymphatic system, affecting the two types of white blood cells (lymphocytes): B-cells and T-cells. Whereas the B-lymphocytes act to neutralize the pathogens, the main job of the T-lymphocytes is to attach to these foreign cells, viruses, or cancerous growths, and directly destroy them.
Compared with other T-cell lymphomas, a distinguishing feature of CTCL is implied by the name: malignant T-cells migrating to, and collecting in, cutaneous tissue. Diagnosis can be challenging, because the initial signs and symptoms are largely skin-related and overlap with those of many other dermatologic disorders. Adding to the challenge, CTCL variants present with overlapping symptomatology, and correct identification of the CTCL subtype is key to both treatment and prognosis. Histopathologic features must be correlated with the clinical presentation to confirm the diagnosis.

Many forms of CTCL are relatively indolent compared with other T-cell lymphomas, but there are aggressive subtypes. This is illustrated by the two most common forms of CTCL: mycosis fungoides and Sézary syndrome. Although mycosis fungoides is considered a slow-growing variant, Sézary syndrome is aggressive and generally has a poor prognosis. Importantly, even the indolent subtypes can progress in some patients and become difficult to manage.

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