Article

Introduction
Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of rare extranodal non-Hodgkin lymphomas that are caused by the accumulation of neoplastic lymphocytes in the skin.^1,2 According to the Surveillance, Epidemiology, and End Results database, a total of 14,942 CTCL cases were recorded between 2000 and 2018.³ The incidence rate for all CTCLs is 8.55 per million and appears to be rising. The causes of such an increase are multifactorial and may be related to better diagnostic tools and increased physician awareness.

The incidence of CTCLs also increases with age. The median age at diagnosis is mid-50s but the incidence of CTCLs is 4-fold greater in patients aged 70 years and older.² Furthermore, men and Black individuals have the highest incidence rates for CTCLs.^2,3 More than 10 types of CTCLs have been identified based on biology, histopathology, and clinical features. CTCL types can be either indolent or aggressive.^1,4 Approximately 75% of all primary cutaneous lymphomas consist of CTCLs, including mycosis fungoides (MF), Sézary syndrome (SS), or CD30+ lymphoproliferative disorders (lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma).

The most common CTCL is MF, a clinically heterogeneous, often indolent disease that tends to progress over years or decades.1 This condition classically presents as cutaneous erythematous patches or plaques in sun-protected areas, ie, demonstrating a bathing suit distribution.⁵ Rarely, MF can present as or progress to more aggressive disease, with infiltrative plaques or tumors. For MF, 5- and 10-year survival ranges from 49% to 100% depending on the stage at diagnosis.¹

The most common aggressive CTCL is SS, characterized by erythroderma, intractable pruritis, and the presence of neoplastic clonal T cells (eg, Sézary cells) in the skin, peripheral blood, and/or lymph nodes, with a Sézary cell absolute count of ≥ 1,000 cells/mm³.^1,2 SS tends to progress more rapidly than MF and has a worse prognosis, with 5-year survival ranging from 10% to 50%.^1,4

Definitive Diagnosis
Diagnosis of CTCL requires the neoplastic T cells be confined to the skin.² Thus, diagnostic evaluation should involve a comprehensive physical examination, skin biopsy, and staging blood tests including a peripheral blood flow cytometry if indicated. Sometimes, radiologic imaging is needed, and if there are any abnormalities found on staging blood tests or imaging, lymph node and bone marrow biopsy may be necessary.¹

MF
MF mimics a wide variety of dermatological diseases, with nearly 50 different clinical entities in the differential, making diagnosis challenging.⁵ Clinical findings are heterogenous, and symptoms may be attributed to benign diseases, eg, eczema, or psoriasis. Pathological features may be nonspecific and subtle in the early stages of the disease and overlap with reactive processes; therefore, multiple biopsies performed during the disease course may be required to reach a definitive diagnosis. Creating a further challenge is the potential for skin-directed therapies (such as topical steroids) to interfere with pathological assessment at the time of biopsy.² Thus, obtaining a definitive diagnosis for MF, particularly in the patch or plaque stage, could take a median of 4 years but can take up to 4 decades.^2,5

A definitive diagnosis for MF can be made using clinical and histopathological features. Possible ancillary studies (if indicated) include determination of T-cell clonality by polymerase chain reaction or next-generation sequencing methods, and assessment for aberrant loss of T-cell antigen expression by immunohistochemical staining.²

SS
Clinical features of SS may be similar to erythrodermic inflammatory dermatoses, and thus the gold standard for diagnosis is peripheral blood involvement and assessing for clonally related neoplastic T-cell populations.¹ Histopathological findings on skin biopsy are often nonspecific.⁴ The currently proposed International Society for Cutaneous Lymphomas criteria for SS integrate clinical, histopathological, immunophenotyping, and molecular studies.²

Benefits of a Multidisciplinary Team Care Approach
Early-stage MF with limited disease can be managed by a dermatologist, but advanced cases often benefit from a multidisciplinary team care model, including hematology-oncology, dermatology, and radiation oncology.^5,6 Several different CTCL care models exist that incorporate resource allocation, staffing availability, and institutional practices developed over time. Regardless of whether care is delivered in a specialized CTCL clinic or a community practice setting, a multidisciplinary team care approach is crucial for patients with advanced-stage CTCL. Dermatologists, hematologist-oncologists, and radiation oncologists may see a patient together or separately, depending on clinical context, and collaborate to formulate the assessment, treatment plan, and address the patient’s questions and concerns. In addition, supportive staff including patient assistance coordinators, pharmacists, behavior health specialists, and palliative care specialists may be included to address the patients’ mental health needs as considerable morbidity from pain, itching, and disfigurement occurs with MF and SS—putting patients at a greater risk for social isolation and depression.⁷

There are several benefits to using a multidisciplinary team care model for managing CTCLs. Different specialties can provide various services and treatment options for patients to consider. Dermatologists perform skin biopsies to monitor disease progression and can administer skin-directed treatments such as phototherapy; radiation oncologists can administer radiation treatment; and oncologists can administer systemic therapies that are outside the scope of dermatology.⁸ The coordination of specialty visits can improve patient satisfaction.

Treatment Goals and Disease Management
Goals for treatment include delaying progression, reducing disease burden, and improving or preserving quality of life.⁵ Decision-making for treating CTCLs should involve preserving potential active treatments for when they are needed during an extended disease course, and mitigating associated burdens of logistical, financial, and physical toxicity.¹

A variety of therapeutic modalities are available for CTCL that target tumor cells and boost antitumor responses, including topical therapies, phototherapy, radiation, chemotherapy, retinoids, and immune-modulating drugs (Table). Because no specific driver mutations have been identified for CTCLs, recent targeted therapy development has focused on various immunomodulators, small molecule inhibitors, monoclonal antibodies, and antibody-drug conjugates.¹ Lastly, for high-risk patients with persistent disease or disease that is refractory to multiple previous therapies, allogenic hematopoietic stem cell transplantation as a potential therapy to induce durable remission may be considered, with careful attention paid to the timing of its use as well as disease and patient characteristics.⁹ 

Table. Therapies for CTCL Care^9,10,a

Alternatively for early-stage MF, a “watch-and-wait” approach depending on the site of lesions and disease evolution may be an option, as this approach is not associated with a worsening of the disease course or survival.¹ Furthermore, aggressive treatments during early stages have not been found to modify the disease course or survival, emphasizing the need for tailoring treatments based on the extent of involvement of the skin and extracutaneous sites.^1,10 New strategies in development to treat CTCL include immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapies. Both strategies focus on engaging the immune system to better combat lymphoma.^11,12 

Outlook for Patients With CTCL
Using a multidisciplinary care approach is the optimal way to deliver the complex care required for CTCL.⁵ Such an approach can reduce the time to a definitive diagnosis and accurately stage and risk-stratify the disease. A stage-based treatment approach using sequential therapies in an escalated fashion can help reserve active treatments for advanced disease management and maintain quality of life for patients with CTCL.^1,2

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Introduction
Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of rare extranodal non-Hodgkin lymphomas that are caused by the accumulation of neoplastic lymphocytes in the skin.^1,2 According to the Surveillance, Epidemiology, and End Results database, a total of 14,942 CTCL cases were recorded between 2000 and 2018.³ The incidence rate for all CTCLs is 8.55 per million and appears to be rising. The causes of such an increase are multifactorial and may be related to better diagnostic tools and increased physician awareness.

The incidence of CTCLs also increases with age. The median age at diagnosis is mid-50s but the incidence of CTCLs is 4-fold greater in patients aged 70 years and older.² Furthermore, men and Black individuals have the highest incidence rates for CTCLs.^2,3 More than 10 types of CTCLs have been identified based on biology, histopathology, and clinical features. CTCL types can be either indolent or aggressive.^1,4 Approximately 75% of all primary cutaneous lymphomas consist of CTCLs, including mycosis fungoides (MF), Sézary syndrome (SS), or CD30+ lymphoproliferative disorders (lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma).

The most common CTCL is MF, a clinically heterogeneous, often indolent disease that tends to progress over years or decades.1 This condition classically presents as cutaneous erythematous patches or plaques in sun-protected areas, ie, demonstrating a bathing suit distribution.⁵ Rarely, MF can present as or progress to more aggressive disease, with infiltrative plaques or tumors. For MF, 5- and 10-year survival ranges from 49% to 100% depending on the stage at diagnosis.¹

The most common aggressive CTCL is SS, characterized by erythroderma, intractable pruritis, and the presence of neoplastic clonal T cells (eg, Sézary cells) in the skin, peripheral blood, and/or lymph nodes, with a Sézary cell absolute count of ≥ 1,000 cells/mm³.^1,2 SS tends to progress more rapidly than MF and has a worse prognosis, with 5-year survival ranging from 10% to 50%.^1,4

Definitive Diagnosis
Diagnosis of CTCL requires the neoplastic T cells be confined to the skin.² Thus, diagnostic evaluation should involve a comprehensive physical examination, skin biopsy, and staging blood tests including a peripheral blood flow cytometry if indicated. Sometimes, radiologic imaging is needed, and if there are any abnormalities found on staging blood tests or imaging, lymph node and bone marrow biopsy may be necessary.¹

MF
MF mimics a wide variety of dermatological diseases, with nearly 50 different clinical entities in the differential, making diagnosis challenging.⁵ Clinical findings are heterogenous, and symptoms may be attributed to benign diseases, eg, eczema, or psoriasis. Pathological features may be nonspecific and subtle in the early stages of the disease and overlap with reactive processes; therefore, multiple biopsies performed during the disease course may be required to reach a definitive diagnosis. Creating a further challenge is the potential for skin-directed therapies (such as topical steroids) to interfere with pathological assessment at the time of biopsy.² Thus, obtaining a definitive diagnosis for MF, particularly in the patch or plaque stage, could take a median of 4 years but can take up to 4 decades.^2,5

A definitive diagnosis for MF can be made using clinical and histopathological features. Possible ancillary studies (if indicated) include determination of T-cell clonality by polymerase chain reaction or next-generation sequencing methods, and assessment for aberrant loss of T-cell antigen expression by immunohistochemical staining.²

SS
Clinical features of SS may be similar to erythrodermic inflammatory dermatoses, and thus the gold standard for diagnosis is peripheral blood involvement and assessing for clonally related neoplastic T-cell populations.¹ Histopathological findings on skin biopsy are often nonspecific.⁴ The currently proposed International Society for Cutaneous Lymphomas criteria for SS integrate clinical, histopathological, immunophenotyping, and molecular studies.²

Benefits of a Multidisciplinary Team Care Approach
Early-stage MF with limited disease can be managed by a dermatologist, but advanced cases often benefit from a multidisciplinary team care model, including hematology-oncology, dermatology, and radiation oncology.^5,6 Several different CTCL care models exist that incorporate resource allocation, staffing availability, and institutional practices developed over time. Regardless of whether care is delivered in a specialized CTCL clinic or a community practice setting, a multidisciplinary team care approach is crucial for patients with advanced-stage CTCL. Dermatologists, hematologist-oncologists, and radiation oncologists may see a patient together or separately, depending on clinical context, and collaborate to formulate the assessment, treatment plan, and address the patient’s questions and concerns. In addition, supportive staff including patient assistance coordinators, pharmacists, behavior health specialists, and palliative care specialists may be included to address the patients’ mental health needs as considerable morbidity from pain, itching, and disfigurement occurs with MF and SS—putting patients at a greater risk for social isolation and depression.⁷

There are several benefits to using a multidisciplinary team care model for managing CTCLs. Different specialties can provide various services and treatment options for patients to consider. Dermatologists perform skin biopsies to monitor disease progression and can administer skin-directed treatments such as phototherapy; radiation oncologists can administer radiation treatment; and oncologists can administer systemic therapies that are outside the scope of dermatology.⁸ The coordination of specialty visits can improve patient satisfaction.

Treatment Goals and Disease Management
Goals for treatment include delaying progression, reducing disease burden, and improving or preserving quality of life.⁵ Decision-making for treating CTCLs should involve preserving potential active treatments for when they are needed during an extended disease course, and mitigating associated burdens of logistical, financial, and physical toxicity.¹

A variety of therapeutic modalities are available for CTCL that target tumor cells and boost antitumor responses, including topical therapies, phototherapy, radiation, chemotherapy, retinoids, and immune-modulating drugs (Table). Because no specific driver mutations have been identified for CTCLs, recent targeted therapy development has focused on various immunomodulators, small molecule inhibitors, monoclonal antibodies, and antibody-drug conjugates.¹ Lastly, for high-risk patients with persistent disease or disease that is refractory to multiple previous therapies, allogenic hematopoietic stem cell transplantation as a potential therapy to induce durable remission may be considered, with careful attention paid to the timing of its use as well as disease and patient characteristics.⁹ 

Table. Therapies for CTCL Care^9,10,a

Alternatively for early-stage MF, a “watch-and-wait” approach depending on the site of lesions and disease evolution may be an option, as this approach is not associated with a worsening of the disease course or survival.¹ Furthermore, aggressive treatments during early stages have not been found to modify the disease course or survival, emphasizing the need for tailoring treatments based on the extent of involvement of the skin and extracutaneous sites.^1,10 New strategies in development to treat CTCL include immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapies. Both strategies focus on engaging the immune system to better combat lymphoma.^11,12 

Outlook for Patients With CTCL
Using a multidisciplinary care approach is the optimal way to deliver the complex care required for CTCL.⁵ Such an approach can reduce the time to a definitive diagnosis and accurately stage and risk-stratify the disease. A stage-based treatment approach using sequential therapies in an escalated fashion can help reserve active treatments for advanced disease management and maintain quality of life for patients with CTCL.^1,2

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Introduction
Cutaneous T-cell lymphomas (CTCL) are a heterogenous group of rare extranodal non-Hodgkin lymphomas that are caused by the accumulation of neoplastic lymphocytes in the skin.^1,2 According to the Surveillance, Epidemiology, and End Results database, a total of 14,942 CTCL cases were recorded between 2000 and 2018.³ The incidence rate for all CTCLs is 8.55 per million and appears to be rising. The causes of such an increase are multifactorial and may be related to better diagnostic tools and increased physician awareness.

The incidence of CTCLs also increases with age. The median age at diagnosis is mid-50s but the incidence of CTCLs is 4-fold greater in patients aged 70 years and older.² Furthermore, men and Black individuals have the highest incidence rates for CTCLs.^2,3 More than 10 types of CTCLs have been identified based on biology, histopathology, and clinical features. CTCL types can be either indolent or aggressive.^1,4 Approximately 75% of all primary cutaneous lymphomas consist of CTCLs, including mycosis fungoides (MF), Sézary syndrome (SS), or CD30+ lymphoproliferative disorders (lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma).

The most common CTCL is MF, a clinically heterogeneous, often indolent disease that tends to progress over years or decades.1 This condition classically presents as cutaneous erythematous patches or plaques in sun-protected areas, ie, demonstrating a bathing suit distribution.⁵ Rarely, MF can present as or progress to more aggressive disease, with infiltrative plaques or tumors. For MF, 5- and 10-year survival ranges from 49% to 100% depending on the stage at diagnosis.¹

The most common aggressive CTCL is SS, characterized by erythroderma, intractable pruritis, and the presence of neoplastic clonal T cells (eg, Sézary cells) in the skin, peripheral blood, and/or lymph nodes, with a Sézary cell absolute count of ≥ 1,000 cells/mm³.^1,2 SS tends to progress more rapidly than MF and has a worse prognosis, with 5-year survival ranging from 10% to 50%.^1,4

Definitive Diagnosis
Diagnosis of CTCL requires the neoplastic T cells be confined to the skin.² Thus, diagnostic evaluation should involve a comprehensive physical examination, skin biopsy, and staging blood tests including a peripheral blood flow cytometry if indicated. Sometimes, radiologic imaging is needed, and if there are any abnormalities found on staging blood tests or imaging, lymph node and bone marrow biopsy may be necessary.¹

MF
MF mimics a wide variety of dermatological diseases, with nearly 50 different clinical entities in the differential, making diagnosis challenging.⁵ Clinical findings are heterogenous, and symptoms may be attributed to benign diseases, eg, eczema, or psoriasis. Pathological features may be nonspecific and subtle in the early stages of the disease and overlap with reactive processes; therefore, multiple biopsies performed during the disease course may be required to reach a definitive diagnosis. Creating a further challenge is the potential for skin-directed therapies (such as topical steroids) to interfere with pathological assessment at the time of biopsy.² Thus, obtaining a definitive diagnosis for MF, particularly in the patch or plaque stage, could take a median of 4 years but can take up to 4 decades.^2,5

A definitive diagnosis for MF can be made using clinical and histopathological features. Possible ancillary studies (if indicated) include determination of T-cell clonality by polymerase chain reaction or next-generation sequencing methods, and assessment for aberrant loss of T-cell antigen expression by immunohistochemical staining.²

SS
Clinical features of SS may be similar to erythrodermic inflammatory dermatoses, and thus the gold standard for diagnosis is peripheral blood involvement and assessing for clonally related neoplastic T-cell populations.¹ Histopathological findings on skin biopsy are often nonspecific.⁴ The currently proposed International Society for Cutaneous Lymphomas criteria for SS integrate clinical, histopathological, immunophenotyping, and molecular studies.²

Benefits of a Multidisciplinary Team Care Approach
Early-stage MF with limited disease can be managed by a dermatologist, but advanced cases often benefit from a multidisciplinary team care model, including hematology-oncology, dermatology, and radiation oncology.^5,6 Several different CTCL care models exist that incorporate resource allocation, staffing availability, and institutional practices developed over time. Regardless of whether care is delivered in a specialized CTCL clinic or a community practice setting, a multidisciplinary team care approach is crucial for patients with advanced-stage CTCL. Dermatologists, hematologist-oncologists, and radiation oncologists may see a patient together or separately, depending on clinical context, and collaborate to formulate the assessment, treatment plan, and address the patient’s questions and concerns. In addition, supportive staff including patient assistance coordinators, pharmacists, behavior health specialists, and palliative care specialists may be included to address the patients’ mental health needs as considerable morbidity from pain, itching, and disfigurement occurs with MF and SS—putting patients at a greater risk for social isolation and depression.⁷

There are several benefits to using a multidisciplinary team care model for managing CTCLs. Different specialties can provide various services and treatment options for patients to consider. Dermatologists perform skin biopsies to monitor disease progression and can administer skin-directed treatments such as phototherapy; radiation oncologists can administer radiation treatment; and oncologists can administer systemic therapies that are outside the scope of dermatology.⁸ The coordination of specialty visits can improve patient satisfaction.

Treatment Goals and Disease Management
Goals for treatment include delaying progression, reducing disease burden, and improving or preserving quality of life.⁵ Decision-making for treating CTCLs should involve preserving potential active treatments for when they are needed during an extended disease course, and mitigating associated burdens of logistical, financial, and physical toxicity.¹

A variety of therapeutic modalities are available for CTCL that target tumor cells and boost antitumor responses, including topical therapies, phototherapy, radiation, chemotherapy, retinoids, and immune-modulating drugs (Table). Because no specific driver mutations have been identified for CTCLs, recent targeted therapy development has focused on various immunomodulators, small molecule inhibitors, monoclonal antibodies, and antibody-drug conjugates.¹ Lastly, for high-risk patients with persistent disease or disease that is refractory to multiple previous therapies, allogenic hematopoietic stem cell transplantation as a potential therapy to induce durable remission may be considered, with careful attention paid to the timing of its use as well as disease and patient characteristics.⁹ 

Table. Therapies for CTCL Care^9,10,a

Alternatively for early-stage MF, a “watch-and-wait” approach depending on the site of lesions and disease evolution may be an option, as this approach is not associated with a worsening of the disease course or survival.¹ Furthermore, aggressive treatments during early stages have not been found to modify the disease course or survival, emphasizing the need for tailoring treatments based on the extent of involvement of the skin and extracutaneous sites.^1,10 New strategies in development to treat CTCL include immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapies. Both strategies focus on engaging the immune system to better combat lymphoma.^11,12 

Outlook for Patients With CTCL
Using a multidisciplinary care approach is the optimal way to deliver the complex care required for CTCL.⁵ Such an approach can reduce the time to a definitive diagnosis and accurately stage and risk-stratify the disease. A stage-based treatment approach using sequential therapies in an escalated fashion can help reserve active treatments for advanced disease management and maintain quality of life for patients with CTCL.^1,2

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Rare cancers account for 25% to 30% of all cancer diagnoses and approximately 25% of all cancer deaths, thereby posing a significant public health burden.¹ Recognizing the need for action to address this health crisis, the National Organization for Rare Disorders (NORD) established the Rare Cancer Coalition in 2017 to alleviate the challenges faced by people living with rare cancers. Since its inception, the Rare Cancer Coalition has reached millions of people through patient and caregiver education sessions, healthcare provider education, and public awareness campaigns. Since its inception, the Rare Cancer Coalition has reached millions of people through patient and caregiver education sessions, healthcare provider education, and public awareness campaigns. The Coalition Members have had an impact on other rare cancer advocacy groups, contributed to medical publications, and provided collaborative networking opportunities among patients, advocates and researchers.

Thanks to successful advocacy by the Rare Cancer Coalition, the United States Congress established “Rare Cancer Day.” This event takes place annually on September 30 and brings global awareness to rare cancers through mass media and public events. In recognition of Rare Cancer Day 2024, NORD focused its public education on the importance of patient participation in rare cancer research. 

NORD and the Rare Cancer Coalition are deeply committed to addressing the unique challenges faced by the rare cancer community. Moving forward, we will focus on promoting the development of innovative and effective treatments, enhancing access to diagnostic testing, advancing new technologies, and fostering research that leads to improved medical approaches for patients with rare cancers.

To that end, we are pleased to present the 2024 Rare Disease Report: Hematology and Oncology in collaboration with our partners at MDedge. This issue will highlight some of the latest advances in rare cancer research, diagnosis, and treatments that are providing new hope for improved outcomes. In this issue, you will find articles that cover recent discoveries on specific rare cancers, including:

• The promise of mTOR inhibitors in improving malignant PEComas
• How novel immunotherapies are demonstrating the potential for improved outcomes for large cell neuroendocrine carcinoma of the lung
• Potential paradigm shifts in the treatment of glioblastoma leveraging CAR T-cell therapies and targeted inhibitors
• Future directions in the treatment of gallbladder cancer with molecular profiling, immunotherapies, and targeted treatments
• The benefits of a multidisciplinary approach in addressing cutaneous T-cell lymphomas
• The evolving role of JAK inhibitors in managing symptoms of myelofibrosis
• Advancements in staging and tailored treatments for hepatoblastoma
• And more!

We hope these articles will enhance your knowledge and enrich your day-to-day clinical practices. We invite you to explore NORD resources including digital CME sessions and disease-specific reports written in accessible language for patients and families. Additionally, you can sign up for our quarterly Caring for Rare newsletter, for timely updates on rare diseases. 

Thank you for your commitment to advancing care for rare cancer patients. Your dedication to staying informed is vital for improving patient outcomes.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Rare cancers account for 25% to 30% of all cancer diagnoses and approximately 25% of all cancer deaths, thereby posing a significant public health burden.¹ Recognizing the need for action to address this health crisis, the National Organization for Rare Disorders (NORD) established the Rare Cancer Coalition in 2017 to alleviate the challenges faced by people living with rare cancers. Since its inception, the Rare Cancer Coalition has reached millions of people through patient and caregiver education sessions, healthcare provider education, and public awareness campaigns. Since its inception, the Rare Cancer Coalition has reached millions of people through patient and caregiver education sessions, healthcare provider education, and public awareness campaigns. The Coalition Members have had an impact on other rare cancer advocacy groups, contributed to medical publications, and provided collaborative networking opportunities among patients, advocates and researchers.

Thanks to successful advocacy by the Rare Cancer Coalition, the United States Congress established “Rare Cancer Day.” This event takes place annually on September 30 and brings global awareness to rare cancers through mass media and public events. In recognition of Rare Cancer Day 2024, NORD focused its public education on the importance of patient participation in rare cancer research. 

NORD and the Rare Cancer Coalition are deeply committed to addressing the unique challenges faced by the rare cancer community. Moving forward, we will focus on promoting the development of innovative and effective treatments, enhancing access to diagnostic testing, advancing new technologies, and fostering research that leads to improved medical approaches for patients with rare cancers.

To that end, we are pleased to present the 2024 Rare Disease Report: Hematology and Oncology in collaboration with our partners at MDedge. This issue will highlight some of the latest advances in rare cancer research, diagnosis, and treatments that are providing new hope for improved outcomes. In this issue, you will find articles that cover recent discoveries on specific rare cancers, including:

• The promise of mTOR inhibitors in improving malignant PEComas
• How novel immunotherapies are demonstrating the potential for improved outcomes for large cell neuroendocrine carcinoma of the lung
• Potential paradigm shifts in the treatment of glioblastoma leveraging CAR T-cell therapies and targeted inhibitors
• Future directions in the treatment of gallbladder cancer with molecular profiling, immunotherapies, and targeted treatments
• The benefits of a multidisciplinary approach in addressing cutaneous T-cell lymphomas
• The evolving role of JAK inhibitors in managing symptoms of myelofibrosis
• Advancements in staging and tailored treatments for hepatoblastoma
• And more!

We hope these articles will enhance your knowledge and enrich your day-to-day clinical practices. We invite you to explore NORD resources including digital CME sessions and disease-specific reports written in accessible language for patients and families. Additionally, you can sign up for our quarterly Caring for Rare newsletter, for timely updates on rare diseases. 

Thank you for your commitment to advancing care for rare cancer patients. Your dedication to staying informed is vital for improving patient outcomes.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Rare cancers account for 25% to 30% of all cancer diagnoses and approximately 25% of all cancer deaths, thereby posing a significant public health burden.¹ Recognizing the need for action to address this health crisis, the National Organization for Rare Disorders (NORD) established the Rare Cancer Coalition in 2017 to alleviate the challenges faced by people living with rare cancers. Since its inception, the Rare Cancer Coalition has reached millions of people through patient and caregiver education sessions, healthcare provider education, and public awareness campaigns. Since its inception, the Rare Cancer Coalition has reached millions of people through patient and caregiver education sessions, healthcare provider education, and public awareness campaigns. The Coalition Members have had an impact on other rare cancer advocacy groups, contributed to medical publications, and provided collaborative networking opportunities among patients, advocates and researchers.

Thanks to successful advocacy by the Rare Cancer Coalition, the United States Congress established “Rare Cancer Day.” This event takes place annually on September 30 and brings global awareness to rare cancers through mass media and public events. In recognition of Rare Cancer Day 2024, NORD focused its public education on the importance of patient participation in rare cancer research. 

NORD and the Rare Cancer Coalition are deeply committed to addressing the unique challenges faced by the rare cancer community. Moving forward, we will focus on promoting the development of innovative and effective treatments, enhancing access to diagnostic testing, advancing new technologies, and fostering research that leads to improved medical approaches for patients with rare cancers.

To that end, we are pleased to present the 2024 Rare Disease Report: Hematology and Oncology in collaboration with our partners at MDedge. This issue will highlight some of the latest advances in rare cancer research, diagnosis, and treatments that are providing new hope for improved outcomes. In this issue, you will find articles that cover recent discoveries on specific rare cancers, including:

• The promise of mTOR inhibitors in improving malignant PEComas
• How novel immunotherapies are demonstrating the potential for improved outcomes for large cell neuroendocrine carcinoma of the lung
• Potential paradigm shifts in the treatment of glioblastoma leveraging CAR T-cell therapies and targeted inhibitors
• Future directions in the treatment of gallbladder cancer with molecular profiling, immunotherapies, and targeted treatments
• The benefits of a multidisciplinary approach in addressing cutaneous T-cell lymphomas
• The evolving role of JAK inhibitors in managing symptoms of myelofibrosis
• Advancements in staging and tailored treatments for hepatoblastoma
• And more!

We hope these articles will enhance your knowledge and enrich your day-to-day clinical practices. We invite you to explore NORD resources including digital CME sessions and disease-specific reports written in accessible language for patients and families. Additionally, you can sign up for our quarterly Caring for Rare newsletter, for timely updates on rare diseases. 

Thank you for your commitment to advancing care for rare cancer patients. Your dedication to staying informed is vital for improving patient outcomes.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

National Organization for Rare Disorders: Strengthening Rare Cancer Advocacy
By Alli Ward
NORD's Rare Cancer Coalition has transformed advocacy and awareness efforts, offering education and fostering research to address the challenges of rare cancers.

Treatment of Glioblastoma: A Potential Shift in Paradigm
By Jeffrey N. Bruce, MD
Immunotherapies and molecular profiling are paving the way for more targeted approaches in treating glioblastoma.

Emerging Insights and Therapeutic Strategies for Large Cell Neuroendocrine Carcinoma of the Lung
By Robert A. Ramirez, DO, FACP, and Aman Chauhan, MD 
New diagnostic tools and precision medicine approaches are addressing the unique challenges of this aggressive neuroendocrine cancer.

Advancements in the Treatment of Malignant PEComas with mTOR Inhibitors
By Richard F. Riedel, MD
The use of mTOR inhibitors marks significant progress in managing advanced malignant PEComas, offering new hope for patients.

Cutaneous T-Cell Lymphomas Update: Benefits of a Multidisciplinary Care Approach
By Jina Chung, MD, and Eric Mou, MD
A multidisciplinary care model ensures optimal outcomes for patients with cutaneous T-cell lymphomas, addressing both medical and emotional needs.

Optimizing Myelofibrosis Care in the Age of JAK Inhibitors
By Douglas Tremblay, MD
JAK inhibitors are central to myelofibrosis management, with personalized strategies helping to navigate resistance and improve quality of life.

Current Management and Future Directions in the Treatment of Gallbladder Cancer
By Ghassan K. Abou-Alfa, MD, MBA, JD, FASCO
Molecular profiling and immunotherapy are reshaping the treatment paradigm for gallbladder cancer, improving survival outcomes.

Improving Prognosis in Hepatoblastoma: Evolving Risk Stratification and Treatment Strategies
By Greg M. Tiao, MD
Risk stratification and individualized therapies are driving progress in treating hepatoblastoma, with promising advancements on the horizon.

National Organization for Rare Disorders: Strengthening Rare Cancer Advocacy
By Alli Ward
NORD's Rare Cancer Coalition has transformed advocacy and awareness efforts, offering education and fostering research to address the challenges of rare cancers.

Treatment of Glioblastoma: A Potential Shift in Paradigm
By Jeffrey N. Bruce, MD
Immunotherapies and molecular profiling are paving the way for more targeted approaches in treating glioblastoma.

Emerging Insights and Therapeutic Strategies for Large Cell Neuroendocrine Carcinoma of the Lung
By Robert A. Ramirez, DO, FACP, and Aman Chauhan, MD 
New diagnostic tools and precision medicine approaches are addressing the unique challenges of this aggressive neuroendocrine cancer.

Advancements in the Treatment of Malignant PEComas with mTOR Inhibitors
By Richard F. Riedel, MD
The use of mTOR inhibitors marks significant progress in managing advanced malignant PEComas, offering new hope for patients.

Cutaneous T-Cell Lymphomas Update: Benefits of a Multidisciplinary Care Approach
By Jina Chung, MD, and Eric Mou, MD
A multidisciplinary care model ensures optimal outcomes for patients with cutaneous T-cell lymphomas, addressing both medical and emotional needs.

Optimizing Myelofibrosis Care in the Age of JAK Inhibitors
By Douglas Tremblay, MD
JAK inhibitors are central to myelofibrosis management, with personalized strategies helping to navigate resistance and improve quality of life.

Current Management and Future Directions in the Treatment of Gallbladder Cancer
By Ghassan K. Abou-Alfa, MD, MBA, JD, FASCO
Molecular profiling and immunotherapy are reshaping the treatment paradigm for gallbladder cancer, improving survival outcomes.

Improving Prognosis in Hepatoblastoma: Evolving Risk Stratification and Treatment Strategies
By Greg M. Tiao, MD
Risk stratification and individualized therapies are driving progress in treating hepatoblastoma, with promising advancements on the horizon.

National Organization for Rare Disorders: Strengthening Rare Cancer Advocacy
By Alli Ward
NORD's Rare Cancer Coalition has transformed advocacy and awareness efforts, offering education and fostering research to address the challenges of rare cancers.

Treatment of Glioblastoma: A Potential Shift in Paradigm
By Jeffrey N. Bruce, MD
Immunotherapies and molecular profiling are paving the way for more targeted approaches in treating glioblastoma.

Emerging Insights and Therapeutic Strategies for Large Cell Neuroendocrine Carcinoma of the Lung
By Robert A. Ramirez, DO, FACP, and Aman Chauhan, MD 
New diagnostic tools and precision medicine approaches are addressing the unique challenges of this aggressive neuroendocrine cancer.

Advancements in the Treatment of Malignant PEComas with mTOR Inhibitors
By Richard F. Riedel, MD
The use of mTOR inhibitors marks significant progress in managing advanced malignant PEComas, offering new hope for patients.

Cutaneous T-Cell Lymphomas Update: Benefits of a Multidisciplinary Care Approach
By Jina Chung, MD, and Eric Mou, MD
A multidisciplinary care model ensures optimal outcomes for patients with cutaneous T-cell lymphomas, addressing both medical and emotional needs.

Optimizing Myelofibrosis Care in the Age of JAK Inhibitors
By Douglas Tremblay, MD
JAK inhibitors are central to myelofibrosis management, with personalized strategies helping to navigate resistance and improve quality of life.

Current Management and Future Directions in the Treatment of Gallbladder Cancer
By Ghassan K. Abou-Alfa, MD, MBA, JD, FASCO
Molecular profiling and immunotherapy are reshaping the treatment paradigm for gallbladder cancer, improving survival outcomes.

Improving Prognosis in Hepatoblastoma: Evolving Risk Stratification and Treatment Strategies
By Greg M. Tiao, MD
Risk stratification and individualized therapies are driving progress in treating hepatoblastoma, with promising advancements on the horizon.

Clinical outcomes of patients with gallbladder cancer have improved considerably with the advent of immunotherapy and targeted therapies. While specialists have gained tremendous insights into the disease over the last 10 years, significant knowledge gaps remain, as relapse rates remain high. Early referral to specialized treatment centers and timely molecular profiling can help guide therapeutic regimen choice and potentially improve patient outcomes.

Insights Into Disease Prevalence and Development
Gallbladder cancer is a rare malignancy with an aggressive course. Most gallbladder cancers are of epithelial origin, with adenocarcinoma being the most common type.¹ Approximately 12,350 new cases of gallbladder cancer and nearby large bile duct cancers are anticipated in 2024 in the United States,² predominantly affecting Southwestern Native Americans.³ The prevalence of gallbladder cancer varies greatly worldwide; rates are highest in South America (mainly in Chile) and Southeast Asia, including Eastern India.^3,4

Multiple factors, including environment and genetics, contribute to the development of gallbladder cancer, which is driven primarily by chronic inflammation.⁵ While there are no defined risk factors, this malignancy is mostly associated with female sex, chronic gallbladder infections, and gallstones.⁴ Some evidence also suggests a dietary association with consuming mustard seed oil.⁶ Exposure to certain environmental toxins or heavy metals may also contribute to disease risk.^1,4

Several genetic alterations have been identified in patients with gallbladder cancer that may be related to disease etiology; these include somatic mutations in the human epidermal growth factor receptor 2 (HER2), Kirsten rat sarcoma viral oncogene homolog (KRAS), and tumor protein p53 (TP53) genes, and many others.^7,8 In addition to somatic mutations, gene overexpression, epigenetic changes, and microRNA-associated changes have also been linked to the disease.³

Challenges in Uncovering a “Hidden” Disease
While most gallbladder cancers are usually detected incidentally, patients may present with symptoms of abdominal pain, discomfort, and biliary obstruction–related symptoms like jaundice, itching, and dark urine.^3,9,10 Cases may initially be misdiagnosed as inflammatory conditions such as cholecystitis or gallbladder stones; as a result, patients may be rushed into an inappropriate or incorrect surgical intervention.¹¹ For these reasons, as well as the tight anatomical location of the gallbladder, cases are often not detected until advanced-stage disease.^3,4

Patients diagnosed in stage 4 with distant metastases have an expected survival rate of less than 1 year,¹² and low referral rates are associated with poor outcomes.¹³ Patients with suspected disease should therefore be referred to a specialized treatment center as soon as possible to confirm a diagnosis and initiate appropriate treatment. Core biopsies can provide histological confirmation, where feasible and safe, followed by imaging to determine extent of the disease.¹⁴

Evolving Management of Localized and Advanced Disease 
Localized disease
Surgery with curative intent is the standard of care in patients with localized disease (Figure).^14,15 Contraindications for resection include distant metastases and occlusion of blood vessels.⁴ Depending on tumor stage, eligible patients may undergo radical cholecystectomy and portal lymphadenectomy, as well as potential liver resection (segments 4b and 5).⁵

Figure. Biliary Tract Cancers (BTCs): Diagnosis and Management Algorithm¹⁴

As the nonencapsulated nature of the gallbladder renders local extension very likely, a peri-adjuvant approach including neoadjuvant and adjuvant arms should be initiated. Standard chemotherapy regimens may include capecitabine or gemcitabine + cisplatin/capecitabine.^16,17

Advanced disease
Systemic therapy remains key in the setting of locally advanced or metastatic disease. In August 2024, the National Comprehensive Cancer Network (NCCN) updated its guidelines to strongly recommend durvalumab + gemcitabine + cisplatin or pembrolizumab + gemcitabine + cisplatin as the preferred regimens for primary treatment of these patients.¹⁷ Other regimens to consider based on both NCCN and European Society of Medical Oncology (ESMO) guidelines include gemcitabine + cisplatin or capecitabine + oxaliplatin.^17,18 In addition, gemcitabine + S-1 (tegafur, gimeracil, and oteracil) may also be considered as part of first-line treatment based on data from clinical trials conducted in Japan.¹⁹ FOLFOX (folinic acid, fluorouracil, and oxaliplatin) is recommended for second-line treatment.¹⁶

While the American Society of Clinical Oncology (ASCO) guidelines are yet to be published, they have previously reviewed data on several potential novel agents and targeted therapies for first-line treatment.²⁰

The addition of immunotherapies such as checkpoint inhibitors to the treatment algorithm has been monumental for the treatment of advanced gallbladder cancer. Durvalumab and pembrolizumab, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PDL-1) receptor inhibitors, in combination with gemcitabine + cisplatin, significantly improve overall survival compared to gemcitabine + cisplatin alone.^17,21,22 These regimens are strongly recommended as first-line therapy in eligible patients who have not previously been treated with a checkpoint inhibitor.

Biopsies should be performed as early as possible in all patients with unresectable or metastatic disease for genomic profiling. Next-generation sequencing can help inform response to targeted therapies in testing by identifying genetic mutations, potentially improving treatment response.^1,23

In certain circumstances, patients with genetic mutations are eligible for molecularly targeted therapies¹⁷:

Unresectable or metastatic disease:

• Neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive tumors: entrectinib, larotrectinib, or repotrectinib 
• High mutational burden (TMB-H) tumors: nivolumab + ipilimumab

Following disease progression:

• B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) V600E-mutated tumors: dabrafenib + trametinib
• Cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) fusions: futibatinib + pemigatinib
• Cholangiocarcinoma with rearrangements or isocitrate dehydrogenase 1 (IDH1) mutations: ivosidenib 

It is important to note that further development of adjuvant strategies is greatly needed to better guide management across disease stages.¹⁶

Therapeutic candidates in testing
Despite the advancements achieved with immunotherapies and targeted treatments, therapeutic options have remained comparable to those of other biliary tumors such as intrahepatic cholangiocarcinoma. However, some novel candidates currently being evaluated in clinical trials have shown promise^24-26:

HER2: Overexpression of the HER2 protein in gallbladder cancer causes abnormal cell survival and proliferation. Initial clinical trial data have suggested that agents targeting HER2 may improve outcomes in patients with advanced gallbladder cancer who harbor somatic HER2 mutations. In fact, the anti-HER2 agent zanidatamab provided clinical benefit and was well tolerated in patients with treatment-refractory, HER2-positive biliary tract cancer in a phase 2 single-arm trial.

Vascular endothelial growth factor (VEGF): The VEGF/ VEGF receptor pathway may also be a promising target due to its role in regulating epithelial cell differentiation and migration. Phase 2 studies of VEGF antibodies, such as bevacizumab, in combination with standard chemotherapy have demonstrated improved response rates; however, some of these studies have shown mixed results.

Phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR): This key signaling pathway plays an important role in driving cancer growth and metastases. Early trials of an mTOR inhibitor in combination with standard chemotherapy have demonstrated an acceptable tolerability profile with potential signs of clinical benefit.

The immunotherapy landscape for gallbladder cancer may evolve beyond currently approved PD-1/PDL-1 receptor inhibitors with the development of agonist antibodies and chimeric antigen receptor T cell (CAR-T) candidates.²⁷ Novel treatment approaches like vaccines and nanoparticle delivery systems are also under investigation.

Looking Toward the Future
Gallbladder cancer is challenging to detect, and earlier diagnosis is key to improving outcomes. It is critical to refer patients to specialized treatment centers as soon as the disease is suspected. Rapid development in advanced genetic testing and other analytical methods may lead to identification of diagnostic biomarkers to aid in detecting cases sooner.²⁴

Despite the fast-evolving pipeline for therapeutic candidates, greater research is also needed to inform sequencing of chemotherapy regimens with immunotherapy and targeted therapy to achieve favorable long-term outcomes.²⁷ As new candidates are approved, management may become remain less than ideal without this crucial guidance.

We hope the future will bring the opportunity to provide more tailored treatments to patients with novel candidates that can further engage the immune system beyond currently identified targets.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Clinical outcomes of patients with gallbladder cancer have improved considerably with the advent of immunotherapy and targeted therapies. While specialists have gained tremendous insights into the disease over the last 10 years, significant knowledge gaps remain, as relapse rates remain high. Early referral to specialized treatment centers and timely molecular profiling can help guide therapeutic regimen choice and potentially improve patient outcomes.

Insights Into Disease Prevalence and Development
Gallbladder cancer is a rare malignancy with an aggressive course. Most gallbladder cancers are of epithelial origin, with adenocarcinoma being the most common type.¹ Approximately 12,350 new cases of gallbladder cancer and nearby large bile duct cancers are anticipated in 2024 in the United States,² predominantly affecting Southwestern Native Americans.³ The prevalence of gallbladder cancer varies greatly worldwide; rates are highest in South America (mainly in Chile) and Southeast Asia, including Eastern India.^3,4

Multiple factors, including environment and genetics, contribute to the development of gallbladder cancer, which is driven primarily by chronic inflammation.⁵ While there are no defined risk factors, this malignancy is mostly associated with female sex, chronic gallbladder infections, and gallstones.⁴ Some evidence also suggests a dietary association with consuming mustard seed oil.⁶ Exposure to certain environmental toxins or heavy metals may also contribute to disease risk.^1,4

Several genetic alterations have been identified in patients with gallbladder cancer that may be related to disease etiology; these include somatic mutations in the human epidermal growth factor receptor 2 (HER2), Kirsten rat sarcoma viral oncogene homolog (KRAS), and tumor protein p53 (TP53) genes, and many others.^7,8 In addition to somatic mutations, gene overexpression, epigenetic changes, and microRNA-associated changes have also been linked to the disease.³

Challenges in Uncovering a “Hidden” Disease
While most gallbladder cancers are usually detected incidentally, patients may present with symptoms of abdominal pain, discomfort, and biliary obstruction–related symptoms like jaundice, itching, and dark urine.^3,9,10 Cases may initially be misdiagnosed as inflammatory conditions such as cholecystitis or gallbladder stones; as a result, patients may be rushed into an inappropriate or incorrect surgical intervention.¹¹ For these reasons, as well as the tight anatomical location of the gallbladder, cases are often not detected until advanced-stage disease.^3,4

Patients diagnosed in stage 4 with distant metastases have an expected survival rate of less than 1 year,¹² and low referral rates are associated with poor outcomes.¹³ Patients with suspected disease should therefore be referred to a specialized treatment center as soon as possible to confirm a diagnosis and initiate appropriate treatment. Core biopsies can provide histological confirmation, where feasible and safe, followed by imaging to determine extent of the disease.¹⁴

Evolving Management of Localized and Advanced Disease 
Localized disease
Surgery with curative intent is the standard of care in patients with localized disease (Figure).^14,15 Contraindications for resection include distant metastases and occlusion of blood vessels.⁴ Depending on tumor stage, eligible patients may undergo radical cholecystectomy and portal lymphadenectomy, as well as potential liver resection (segments 4b and 5).⁵

Figure. Biliary Tract Cancers (BTCs): Diagnosis and Management Algorithm¹⁴

As the nonencapsulated nature of the gallbladder renders local extension very likely, a peri-adjuvant approach including neoadjuvant and adjuvant arms should be initiated. Standard chemotherapy regimens may include capecitabine or gemcitabine + cisplatin/capecitabine.^16,17

Advanced disease
Systemic therapy remains key in the setting of locally advanced or metastatic disease. In August 2024, the National Comprehensive Cancer Network (NCCN) updated its guidelines to strongly recommend durvalumab + gemcitabine + cisplatin or pembrolizumab + gemcitabine + cisplatin as the preferred regimens for primary treatment of these patients.¹⁷ Other regimens to consider based on both NCCN and European Society of Medical Oncology (ESMO) guidelines include gemcitabine + cisplatin or capecitabine + oxaliplatin.^17,18 In addition, gemcitabine + S-1 (tegafur, gimeracil, and oteracil) may also be considered as part of first-line treatment based on data from clinical trials conducted in Japan.¹⁹ FOLFOX (folinic acid, fluorouracil, and oxaliplatin) is recommended for second-line treatment.¹⁶

While the American Society of Clinical Oncology (ASCO) guidelines are yet to be published, they have previously reviewed data on several potential novel agents and targeted therapies for first-line treatment.²⁰

The addition of immunotherapies such as checkpoint inhibitors to the treatment algorithm has been monumental for the treatment of advanced gallbladder cancer. Durvalumab and pembrolizumab, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PDL-1) receptor inhibitors, in combination with gemcitabine + cisplatin, significantly improve overall survival compared to gemcitabine + cisplatin alone.^17,21,22 These regimens are strongly recommended as first-line therapy in eligible patients who have not previously been treated with a checkpoint inhibitor.

Biopsies should be performed as early as possible in all patients with unresectable or metastatic disease for genomic profiling. Next-generation sequencing can help inform response to targeted therapies in testing by identifying genetic mutations, potentially improving treatment response.^1,23

In certain circumstances, patients with genetic mutations are eligible for molecularly targeted therapies¹⁷:

Unresectable or metastatic disease:

• Neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive tumors: entrectinib, larotrectinib, or repotrectinib 
• High mutational burden (TMB-H) tumors: nivolumab + ipilimumab

Following disease progression:

• B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) V600E-mutated tumors: dabrafenib + trametinib
• Cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) fusions: futibatinib + pemigatinib
• Cholangiocarcinoma with rearrangements or isocitrate dehydrogenase 1 (IDH1) mutations: ivosidenib 

It is important to note that further development of adjuvant strategies is greatly needed to better guide management across disease stages.¹⁶

Therapeutic candidates in testing
Despite the advancements achieved with immunotherapies and targeted treatments, therapeutic options have remained comparable to those of other biliary tumors such as intrahepatic cholangiocarcinoma. However, some novel candidates currently being evaluated in clinical trials have shown promise^24-26:

HER2: Overexpression of the HER2 protein in gallbladder cancer causes abnormal cell survival and proliferation. Initial clinical trial data have suggested that agents targeting HER2 may improve outcomes in patients with advanced gallbladder cancer who harbor somatic HER2 mutations. In fact, the anti-HER2 agent zanidatamab provided clinical benefit and was well tolerated in patients with treatment-refractory, HER2-positive biliary tract cancer in a phase 2 single-arm trial.

Vascular endothelial growth factor (VEGF): The VEGF/ VEGF receptor pathway may also be a promising target due to its role in regulating epithelial cell differentiation and migration. Phase 2 studies of VEGF antibodies, such as bevacizumab, in combination with standard chemotherapy have demonstrated improved response rates; however, some of these studies have shown mixed results.

Phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR): This key signaling pathway plays an important role in driving cancer growth and metastases. Early trials of an mTOR inhibitor in combination with standard chemotherapy have demonstrated an acceptable tolerability profile with potential signs of clinical benefit.

The immunotherapy landscape for gallbladder cancer may evolve beyond currently approved PD-1/PDL-1 receptor inhibitors with the development of agonist antibodies and chimeric antigen receptor T cell (CAR-T) candidates.²⁷ Novel treatment approaches like vaccines and nanoparticle delivery systems are also under investigation.

Looking Toward the Future
Gallbladder cancer is challenging to detect, and earlier diagnosis is key to improving outcomes. It is critical to refer patients to specialized treatment centers as soon as the disease is suspected. Rapid development in advanced genetic testing and other analytical methods may lead to identification of diagnostic biomarkers to aid in detecting cases sooner.²⁴

Despite the fast-evolving pipeline for therapeutic candidates, greater research is also needed to inform sequencing of chemotherapy regimens with immunotherapy and targeted therapy to achieve favorable long-term outcomes.²⁷ As new candidates are approved, management may become remain less than ideal without this crucial guidance.

We hope the future will bring the opportunity to provide more tailored treatments to patients with novel candidates that can further engage the immune system beyond currently identified targets.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Clinical outcomes of patients with gallbladder cancer have improved considerably with the advent of immunotherapy and targeted therapies. While specialists have gained tremendous insights into the disease over the last 10 years, significant knowledge gaps remain, as relapse rates remain high. Early referral to specialized treatment centers and timely molecular profiling can help guide therapeutic regimen choice and potentially improve patient outcomes.

Insights Into Disease Prevalence and Development
Gallbladder cancer is a rare malignancy with an aggressive course. Most gallbladder cancers are of epithelial origin, with adenocarcinoma being the most common type.¹ Approximately 12,350 new cases of gallbladder cancer and nearby large bile duct cancers are anticipated in 2024 in the United States,² predominantly affecting Southwestern Native Americans.³ The prevalence of gallbladder cancer varies greatly worldwide; rates are highest in South America (mainly in Chile) and Southeast Asia, including Eastern India.^3,4

Multiple factors, including environment and genetics, contribute to the development of gallbladder cancer, which is driven primarily by chronic inflammation.⁵ While there are no defined risk factors, this malignancy is mostly associated with female sex, chronic gallbladder infections, and gallstones.⁴ Some evidence also suggests a dietary association with consuming mustard seed oil.⁶ Exposure to certain environmental toxins or heavy metals may also contribute to disease risk.^1,4

Several genetic alterations have been identified in patients with gallbladder cancer that may be related to disease etiology; these include somatic mutations in the human epidermal growth factor receptor 2 (HER2), Kirsten rat sarcoma viral oncogene homolog (KRAS), and tumor protein p53 (TP53) genes, and many others.^7,8 In addition to somatic mutations, gene overexpression, epigenetic changes, and microRNA-associated changes have also been linked to the disease.³

Challenges in Uncovering a “Hidden” Disease
While most gallbladder cancers are usually detected incidentally, patients may present with symptoms of abdominal pain, discomfort, and biliary obstruction–related symptoms like jaundice, itching, and dark urine.^3,9,10 Cases may initially be misdiagnosed as inflammatory conditions such as cholecystitis or gallbladder stones; as a result, patients may be rushed into an inappropriate or incorrect surgical intervention.¹¹ For these reasons, as well as the tight anatomical location of the gallbladder, cases are often not detected until advanced-stage disease.^3,4

Patients diagnosed in stage 4 with distant metastases have an expected survival rate of less than 1 year,¹² and low referral rates are associated with poor outcomes.¹³ Patients with suspected disease should therefore be referred to a specialized treatment center as soon as possible to confirm a diagnosis and initiate appropriate treatment. Core biopsies can provide histological confirmation, where feasible and safe, followed by imaging to determine extent of the disease.¹⁴

Evolving Management of Localized and Advanced Disease 
Localized disease
Surgery with curative intent is the standard of care in patients with localized disease (Figure).^14,15 Contraindications for resection include distant metastases and occlusion of blood vessels.⁴ Depending on tumor stage, eligible patients may undergo radical cholecystectomy and portal lymphadenectomy, as well as potential liver resection (segments 4b and 5).⁵

Figure. Biliary Tract Cancers (BTCs): Diagnosis and Management Algorithm¹⁴

As the nonencapsulated nature of the gallbladder renders local extension very likely, a peri-adjuvant approach including neoadjuvant and adjuvant arms should be initiated. Standard chemotherapy regimens may include capecitabine or gemcitabine + cisplatin/capecitabine.^16,17

Advanced disease
Systemic therapy remains key in the setting of locally advanced or metastatic disease. In August 2024, the National Comprehensive Cancer Network (NCCN) updated its guidelines to strongly recommend durvalumab + gemcitabine + cisplatin or pembrolizumab + gemcitabine + cisplatin as the preferred regimens for primary treatment of these patients.¹⁷ Other regimens to consider based on both NCCN and European Society of Medical Oncology (ESMO) guidelines include gemcitabine + cisplatin or capecitabine + oxaliplatin.^17,18 In addition, gemcitabine + S-1 (tegafur, gimeracil, and oteracil) may also be considered as part of first-line treatment based on data from clinical trials conducted in Japan.¹⁹ FOLFOX (folinic acid, fluorouracil, and oxaliplatin) is recommended for second-line treatment.¹⁶

While the American Society of Clinical Oncology (ASCO) guidelines are yet to be published, they have previously reviewed data on several potential novel agents and targeted therapies for first-line treatment.²⁰

The addition of immunotherapies such as checkpoint inhibitors to the treatment algorithm has been monumental for the treatment of advanced gallbladder cancer. Durvalumab and pembrolizumab, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PDL-1) receptor inhibitors, in combination with gemcitabine + cisplatin, significantly improve overall survival compared to gemcitabine + cisplatin alone.^17,21,22 These regimens are strongly recommended as first-line therapy in eligible patients who have not previously been treated with a checkpoint inhibitor.

Biopsies should be performed as early as possible in all patients with unresectable or metastatic disease for genomic profiling. Next-generation sequencing can help inform response to targeted therapies in testing by identifying genetic mutations, potentially improving treatment response.^1,23

In certain circumstances, patients with genetic mutations are eligible for molecularly targeted therapies¹⁷:

Unresectable or metastatic disease:

• Neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive tumors: entrectinib, larotrectinib, or repotrectinib 
• High mutational burden (TMB-H) tumors: nivolumab + ipilimumab

Following disease progression:

• B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) V600E-mutated tumors: dabrafenib + trametinib
• Cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) fusions: futibatinib + pemigatinib
• Cholangiocarcinoma with rearrangements or isocitrate dehydrogenase 1 (IDH1) mutations: ivosidenib 

It is important to note that further development of adjuvant strategies is greatly needed to better guide management across disease stages.¹⁶

Therapeutic candidates in testing
Despite the advancements achieved with immunotherapies and targeted treatments, therapeutic options have remained comparable to those of other biliary tumors such as intrahepatic cholangiocarcinoma. However, some novel candidates currently being evaluated in clinical trials have shown promise^24-26:

HER2: Overexpression of the HER2 protein in gallbladder cancer causes abnormal cell survival and proliferation. Initial clinical trial data have suggested that agents targeting HER2 may improve outcomes in patients with advanced gallbladder cancer who harbor somatic HER2 mutations. In fact, the anti-HER2 agent zanidatamab provided clinical benefit and was well tolerated in patients with treatment-refractory, HER2-positive biliary tract cancer in a phase 2 single-arm trial.

Vascular endothelial growth factor (VEGF): The VEGF/ VEGF receptor pathway may also be a promising target due to its role in regulating epithelial cell differentiation and migration. Phase 2 studies of VEGF antibodies, such as bevacizumab, in combination with standard chemotherapy have demonstrated improved response rates; however, some of these studies have shown mixed results.

Phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR): This key signaling pathway plays an important role in driving cancer growth and metastases. Early trials of an mTOR inhibitor in combination with standard chemotherapy have demonstrated an acceptable tolerability profile with potential signs of clinical benefit.

The immunotherapy landscape for gallbladder cancer may evolve beyond currently approved PD-1/PDL-1 receptor inhibitors with the development of agonist antibodies and chimeric antigen receptor T cell (CAR-T) candidates.²⁷ Novel treatment approaches like vaccines and nanoparticle delivery systems are also under investigation.

Looking Toward the Future
Gallbladder cancer is challenging to detect, and earlier diagnosis is key to improving outcomes. It is critical to refer patients to specialized treatment centers as soon as the disease is suspected. Rapid development in advanced genetic testing and other analytical methods may lead to identification of diagnostic biomarkers to aid in detecting cases sooner.²⁴

Despite the fast-evolving pipeline for therapeutic candidates, greater research is also needed to inform sequencing of chemotherapy regimens with immunotherapy and targeted therapy to achieve favorable long-term outcomes.²⁷ As new candidates are approved, management may become remain less than ideal without this crucial guidance.

We hope the future will bring the opportunity to provide more tailored treatments to patients with novel candidates that can further engage the immune system beyond currently identified targets.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Introduction
Hepatoblastoma accounts for most pediatric liver cancers, but accounts for only 1% of all malignancies in children. Rates of hepatoblastoma have increased gradually over the past 20 years for unclear reasons, but it remains a rare malignancy. In the 1970s, only a small percentage of patients survived long-term. Today, 5-year survival rates range from 65% to over 90%, depending on risk factors, thanks to recent advancements in the understanding and treatment of hepatoblastoma.^1-5 Improved risk stratification has led to better staging and more personalized treatment approaches. To further improve survival, current research is concentrated on improving outcomes in the most challenging patient subsets, such as those with metastatic disease and patients with disease relapse.

Background
Hepatoblastoma is typically diagnosed in the first 2 years of life.⁶ Accounting for more than 60% of pediatric hepatic malignancies worldwide, the incidence of hepatoblastoma is increasing. Results from a study evaluating the incidence between 2001 and 2017 showed a 2% annual increase documented in children aged from birth to 4 years in the United States, climbing to 5.8% annually among children aged 5 to 9 years.² Risk factors for hepatoblastoma include maternal preeclampsia, premature birth, and parental smoking.⁷ The degree to which each of these factors plays a role is uncertain. A genetic etiology is suspected in a minority of hepatoblastoma cases, but it is associated with several genetic diseases, including Beckwith-Weidemann syndrome, familial adenomatous polyposis, and Prader-Willi syndrome.⁸ Genetic mutations in the Wnt signaling pathway that result in the accumulation of beta-catenin have also been found in sporadic, nonfamilial cases.⁹

Although this condition generally presents as a single abdominal mass in the right lobe of the liver, multifocal hepatoblastoma at diagnosis does occur.¹⁰ In most patients, alpha-fetoprotein (AFP) is significantly elevated.¹¹ An estimated 20% of patients present with metastases, which are most commonly found in the lung.¹² While ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) can be used to define the extent of the tumor in the liver, a chest CT is appropriate to look for metastases beyond the liver.¹³

Of the 2 broad histological categories commonly used to characterize hepatoblastoma, the more common epithelial form consists of fetal or embryonal liver cells. The mixed epithelial-mesenchymal form that accounts for 20% to 30% of hepatoblastomas features epithelial and primitive mesenchymal tissue, often with osteoid tissue or cartilage⁶; both have numerous histological subtypes. For example, the epithelial type can be further characterized by a well- or poorly-differentiated appearance, while the mixed type can be subdivided by the presence or absence of teratoid features.

Prior to 2017, there was considerable disparity in the way hepatoblastomas were characterized and staged among the major research consortiums. This issue was addressed when a consortium was established in which pediatric oncology groups pooled their data. The Children’s Hepatic tumors International Collaboration (CHIC) released the PRETEXT (PRETreatment EXTent of disease) approach.^7,14 Based on comprehensive data from 1605 children participating in multicenter trials, the CHIC risk stratification defines and provides risk trees for very low-, low-, intermediate-, and high-risk groups. The most important predictors included AFP levels, patient age, extent of disease in the liver (particularly involving major hepatic veins), and the presence of metastases.

Further improvements to the diagnosis and staging of hepatoblastoma are credited to consensus-based recommendations for imaging that were created in the context of the PRETEXT staging system.¹³ While ultrasound is recommended for the initial approach to diagnosis, this consensus calls for MRI with hepatobiliary contrast to better characterize the lesion and detect satellite lesions. This form of imaging is also recommended for follow-up after treatment, but results should be interpreted in the context of biomarkers, such as AFP levels, pathologic grading, and tumor subtypes.

In patients with the most common familial disorders associated with a predisposition for hepatoblastoma, such as adenomatous polyposis, Beckwith-Weidemann spectrum, or trisomy 18, regular surveillance for hepatoblastoma is recommended during the early years of life.⁸ Characterization of the genetic and molecular features of patients who present with hepatoblastoma might be useful in determining prognosis. Of genetic features, mutations in the CTNNB1 gene are the most common, but several genes in the Wnt pathway are also linked to hepatoblastoma formation.⁹

Along with the progress in subtyping patients by genetics, epigenetics, and molecular features, there is a growing appreciation for the heterogeneity of hepatoblastoma and the likelihood that treatment strategies can be better individualized to improve outcomes in high-risk patients. This progress is expected to accelerate further when results from the results from the Pediatric Hepatic International Tumor Trial (PHITT) are published. These data are expected to be available in 2025, and may help with prognostication and understanding the biology of hepatoblastoma in relation to outcomes.

Treatment Strategies in Hepatoblastoma
For low-grade hepatoblastoma, the first-line therapy is surgery, which can be sufficient for cure without relapse in selected patients with PRETEXT group 1 disease. Although only 40% to 60% of patients have resectable disease at diagnosis,¹⁰ there are several strategies to shrink tumor bulk, particularly chemotherapy due to the relatively high sensitivity of hepatoblastoma to cytotoxic therapies. The intensity of chemotherapy is increased relative to risk.¹¹ For example, cisplatin-based regimens are considered for low-risk patients, while additional therapies, such as doxorubicin, irinotecan, or both, are added in patients at higher risk. Cure is common if these regimens permit a margin-free resection, although relapse does occur in a subset of patients.

If adequate debulking of the tumor cannot be achieved with conventional surgery, liver transplantation is typically offered for patients without extrahepatic disease or after distant metastases have been successfully excised. With liver transplantation and combination therapies to inhibit relapse associated with seeding, long-term survival rates of 80% have been reported.³ Judicious use of transplantation in patients with high-risk disease that raises the potential for relapse has been credited with rates of long-term survival that exceed 80% in some series. However, there is concern of offering transplantation when it is not necessary. In patients who are high risk with multiple lesions in the liver, there is a general agreement that transplantation reduces the likelihood of subsequent relapse; however, as the precision of aggressive resection coupled with effective chemotherapy has improved, there are more patients in whom the optimal choice might not be debated by experts.

Review articles typically cite the likelihood of an overall 5-year survival in patients with hepatoblastoma as being on the order of 80%.¹ This rate includes children with late-onset disease, which is generally associated with a worse prognosis, and patients who eventually experience disease relapse. Survival rates are now likely to be substantially higher, with progress developing better treatment protocols for both groups. In the absence of high-risk features, long-term survival rates of 90% or higher are now being reported in some centers with high relative volumes of hepatoblastoma, regardless of baseline risks. 

PHITT
The rarity of hepatoblastoma poses a significant challenge to conducting prospective studies with sufficient sample sizes to evaluate the overall efficacy of treatments and their effectiveness in patient subgroups based on specific clinical characteristics and disease severity. PHITT is the first international collaborative liver tumors trial to use a consensus approach. Centers in Europe, Japan, and the United States are participating through regional cancer study consortia. The Cincinnati Children’s Hospital and Medical Center, a leader in hepatoblastoma management in the United States, is anchoring this effort for the Children’s Oncology Group. 

In addition to assessing treatment strategies in larger patient cohorts, PHITT is expanding the data available to correlate outcomes across different stages and risk categories based on histological and biological classifications. Hepatoblastoma and hepatocellular carcinoma are being addressed in PHITT, but the design schema for these malignancies differs. For patients enrolled with hepatoblastoma, 4 risk groups have been defined, ranging from very low to high. Within these risk categories, flow charts provide guide selection of treatments based on clinical and disease features.

Cincinnati Children’s Hospital and Medical Center is one of the most active centers for the treatment of hepatoblastoma in the Unites States but manages only 15 to 20 cases of this rare disease per year. PHITT is expected to play a critical role in achieving a high level of valuable data, and the first sets of outcomes from this collaboration are anticipated to be available in early 2025. As the study progresses, meaningful data are expected for the most challenging and some of the rarest hepatoblastoma risk groups.

Summary
The rates of cure are now approaching 100% with surgery and chemotherapy in patients with localized or locally advanced hepatoblastoma. For more advanced, unresectable disease, liver transplantation is effective in most patients, providing high rates of long-term survival. For patients with relapsed disease, advanced treatment protocols at centers with high relative volumes
of hepatoblastoma are now regularly achieving a second remission—many of which are durable. Although prognosis is less favorable in patients who experience a second relapse, long-term survival is achieved even in a proportion of these children. Substantial rates of response and long-term survival have been common in hepatoblastoma diagnosed at early stages, but the recent progress in advanced hepatoblastoma is credited to more aggressive therapies based on a better understanding of the disease characteristics that allows for individualized therapy. There is hope that the larger pool of data becoming available in 2025 from PHITT will prove to be an additional source of information that guides further advances in managing this rare disease.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Introduction
Hepatoblastoma accounts for most pediatric liver cancers, but accounts for only 1% of all malignancies in children. Rates of hepatoblastoma have increased gradually over the past 20 years for unclear reasons, but it remains a rare malignancy. In the 1970s, only a small percentage of patients survived long-term. Today, 5-year survival rates range from 65% to over 90%, depending on risk factors, thanks to recent advancements in the understanding and treatment of hepatoblastoma.^1-5 Improved risk stratification has led to better staging and more personalized treatment approaches. To further improve survival, current research is concentrated on improving outcomes in the most challenging patient subsets, such as those with metastatic disease and patients with disease relapse.

Background
Hepatoblastoma is typically diagnosed in the first 2 years of life.⁶ Accounting for more than 60% of pediatric hepatic malignancies worldwide, the incidence of hepatoblastoma is increasing. Results from a study evaluating the incidence between 2001 and 2017 showed a 2% annual increase documented in children aged from birth to 4 years in the United States, climbing to 5.8% annually among children aged 5 to 9 years.² Risk factors for hepatoblastoma include maternal preeclampsia, premature birth, and parental smoking.⁷ The degree to which each of these factors plays a role is uncertain. A genetic etiology is suspected in a minority of hepatoblastoma cases, but it is associated with several genetic diseases, including Beckwith-Weidemann syndrome, familial adenomatous polyposis, and Prader-Willi syndrome.⁸ Genetic mutations in the Wnt signaling pathway that result in the accumulation of beta-catenin have also been found in sporadic, nonfamilial cases.⁹

Although this condition generally presents as a single abdominal mass in the right lobe of the liver, multifocal hepatoblastoma at diagnosis does occur.¹⁰ In most patients, alpha-fetoprotein (AFP) is significantly elevated.¹¹ An estimated 20% of patients present with metastases, which are most commonly found in the lung.¹² While ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) can be used to define the extent of the tumor in the liver, a chest CT is appropriate to look for metastases beyond the liver.¹³

Of the 2 broad histological categories commonly used to characterize hepatoblastoma, the more common epithelial form consists of fetal or embryonal liver cells. The mixed epithelial-mesenchymal form that accounts for 20% to 30% of hepatoblastomas features epithelial and primitive mesenchymal tissue, often with osteoid tissue or cartilage⁶; both have numerous histological subtypes. For example, the epithelial type can be further characterized by a well- or poorly-differentiated appearance, while the mixed type can be subdivided by the presence or absence of teratoid features.

Prior to 2017, there was considerable disparity in the way hepatoblastomas were characterized and staged among the major research consortiums. This issue was addressed when a consortium was established in which pediatric oncology groups pooled their data. The Children’s Hepatic tumors International Collaboration (CHIC) released the PRETEXT (PRETreatment EXTent of disease) approach.^7,14 Based on comprehensive data from 1605 children participating in multicenter trials, the CHIC risk stratification defines and provides risk trees for very low-, low-, intermediate-, and high-risk groups. The most important predictors included AFP levels, patient age, extent of disease in the liver (particularly involving major hepatic veins), and the presence of metastases.

Further improvements to the diagnosis and staging of hepatoblastoma are credited to consensus-based recommendations for imaging that were created in the context of the PRETEXT staging system.¹³ While ultrasound is recommended for the initial approach to diagnosis, this consensus calls for MRI with hepatobiliary contrast to better characterize the lesion and detect satellite lesions. This form of imaging is also recommended for follow-up after treatment, but results should be interpreted in the context of biomarkers, such as AFP levels, pathologic grading, and tumor subtypes.

In patients with the most common familial disorders associated with a predisposition for hepatoblastoma, such as adenomatous polyposis, Beckwith-Weidemann spectrum, or trisomy 18, regular surveillance for hepatoblastoma is recommended during the early years of life.⁸ Characterization of the genetic and molecular features of patients who present with hepatoblastoma might be useful in determining prognosis. Of genetic features, mutations in the CTNNB1 gene are the most common, but several genes in the Wnt pathway are also linked to hepatoblastoma formation.⁹

Along with the progress in subtyping patients by genetics, epigenetics, and molecular features, there is a growing appreciation for the heterogeneity of hepatoblastoma and the likelihood that treatment strategies can be better individualized to improve outcomes in high-risk patients. This progress is expected to accelerate further when results from the results from the Pediatric Hepatic International Tumor Trial (PHITT) are published. These data are expected to be available in 2025, and may help with prognostication and understanding the biology of hepatoblastoma in relation to outcomes.

Treatment Strategies in Hepatoblastoma
For low-grade hepatoblastoma, the first-line therapy is surgery, which can be sufficient for cure without relapse in selected patients with PRETEXT group 1 disease. Although only 40% to 60% of patients have resectable disease at diagnosis,¹⁰ there are several strategies to shrink tumor bulk, particularly chemotherapy due to the relatively high sensitivity of hepatoblastoma to cytotoxic therapies. The intensity of chemotherapy is increased relative to risk.¹¹ For example, cisplatin-based regimens are considered for low-risk patients, while additional therapies, such as doxorubicin, irinotecan, or both, are added in patients at higher risk. Cure is common if these regimens permit a margin-free resection, although relapse does occur in a subset of patients.

If adequate debulking of the tumor cannot be achieved with conventional surgery, liver transplantation is typically offered for patients without extrahepatic disease or after distant metastases have been successfully excised. With liver transplantation and combination therapies to inhibit relapse associated with seeding, long-term survival rates of 80% have been reported.³ Judicious use of transplantation in patients with high-risk disease that raises the potential for relapse has been credited with rates of long-term survival that exceed 80% in some series. However, there is concern of offering transplantation when it is not necessary. In patients who are high risk with multiple lesions in the liver, there is a general agreement that transplantation reduces the likelihood of subsequent relapse; however, as the precision of aggressive resection coupled with effective chemotherapy has improved, there are more patients in whom the optimal choice might not be debated by experts.

Review articles typically cite the likelihood of an overall 5-year survival in patients with hepatoblastoma as being on the order of 80%.¹ This rate includes children with late-onset disease, which is generally associated with a worse prognosis, and patients who eventually experience disease relapse. Survival rates are now likely to be substantially higher, with progress developing better treatment protocols for both groups. In the absence of high-risk features, long-term survival rates of 90% or higher are now being reported in some centers with high relative volumes of hepatoblastoma, regardless of baseline risks. 

PHITT
The rarity of hepatoblastoma poses a significant challenge to conducting prospective studies with sufficient sample sizes to evaluate the overall efficacy of treatments and their effectiveness in patient subgroups based on specific clinical characteristics and disease severity. PHITT is the first international collaborative liver tumors trial to use a consensus approach. Centers in Europe, Japan, and the United States are participating through regional cancer study consortia. The Cincinnati Children’s Hospital and Medical Center, a leader in hepatoblastoma management in the United States, is anchoring this effort for the Children’s Oncology Group. 

In addition to assessing treatment strategies in larger patient cohorts, PHITT is expanding the data available to correlate outcomes across different stages and risk categories based on histological and biological classifications. Hepatoblastoma and hepatocellular carcinoma are being addressed in PHITT, but the design schema for these malignancies differs. For patients enrolled with hepatoblastoma, 4 risk groups have been defined, ranging from very low to high. Within these risk categories, flow charts provide guide selection of treatments based on clinical and disease features.

Cincinnati Children’s Hospital and Medical Center is one of the most active centers for the treatment of hepatoblastoma in the Unites States but manages only 15 to 20 cases of this rare disease per year. PHITT is expected to play a critical role in achieving a high level of valuable data, and the first sets of outcomes from this collaboration are anticipated to be available in early 2025. As the study progresses, meaningful data are expected for the most challenging and some of the rarest hepatoblastoma risk groups.

Summary
The rates of cure are now approaching 100% with surgery and chemotherapy in patients with localized or locally advanced hepatoblastoma. For more advanced, unresectable disease, liver transplantation is effective in most patients, providing high rates of long-term survival. For patients with relapsed disease, advanced treatment protocols at centers with high relative volumes
of hepatoblastoma are now regularly achieving a second remission—many of which are durable. Although prognosis is less favorable in patients who experience a second relapse, long-term survival is achieved even in a proportion of these children. Substantial rates of response and long-term survival have been common in hepatoblastoma diagnosed at early stages, but the recent progress in advanced hepatoblastoma is credited to more aggressive therapies based on a better understanding of the disease characteristics that allows for individualized therapy. There is hope that the larger pool of data becoming available in 2025 from PHITT will prove to be an additional source of information that guides further advances in managing this rare disease.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Introduction
Hepatoblastoma accounts for most pediatric liver cancers, but accounts for only 1% of all malignancies in children. Rates of hepatoblastoma have increased gradually over the past 20 years for unclear reasons, but it remains a rare malignancy. In the 1970s, only a small percentage of patients survived long-term. Today, 5-year survival rates range from 65% to over 90%, depending on risk factors, thanks to recent advancements in the understanding and treatment of hepatoblastoma.^1-5 Improved risk stratification has led to better staging and more personalized treatment approaches. To further improve survival, current research is concentrated on improving outcomes in the most challenging patient subsets, such as those with metastatic disease and patients with disease relapse.

Background
Hepatoblastoma is typically diagnosed in the first 2 years of life.⁶ Accounting for more than 60% of pediatric hepatic malignancies worldwide, the incidence of hepatoblastoma is increasing. Results from a study evaluating the incidence between 2001 and 2017 showed a 2% annual increase documented in children aged from birth to 4 years in the United States, climbing to 5.8% annually among children aged 5 to 9 years.² Risk factors for hepatoblastoma include maternal preeclampsia, premature birth, and parental smoking.⁷ The degree to which each of these factors plays a role is uncertain. A genetic etiology is suspected in a minority of hepatoblastoma cases, but it is associated with several genetic diseases, including Beckwith-Weidemann syndrome, familial adenomatous polyposis, and Prader-Willi syndrome.⁸ Genetic mutations in the Wnt signaling pathway that result in the accumulation of beta-catenin have also been found in sporadic, nonfamilial cases.⁹

Although this condition generally presents as a single abdominal mass in the right lobe of the liver, multifocal hepatoblastoma at diagnosis does occur.¹⁰ In most patients, alpha-fetoprotein (AFP) is significantly elevated.¹¹ An estimated 20% of patients present with metastases, which are most commonly found in the lung.¹² While ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) can be used to define the extent of the tumor in the liver, a chest CT is appropriate to look for metastases beyond the liver.¹³

Of the 2 broad histological categories commonly used to characterize hepatoblastoma, the more common epithelial form consists of fetal or embryonal liver cells. The mixed epithelial-mesenchymal form that accounts for 20% to 30% of hepatoblastomas features epithelial and primitive mesenchymal tissue, often with osteoid tissue or cartilage⁶; both have numerous histological subtypes. For example, the epithelial type can be further characterized by a well- or poorly-differentiated appearance, while the mixed type can be subdivided by the presence or absence of teratoid features.

Prior to 2017, there was considerable disparity in the way hepatoblastomas were characterized and staged among the major research consortiums. This issue was addressed when a consortium was established in which pediatric oncology groups pooled their data. The Children’s Hepatic tumors International Collaboration (CHIC) released the PRETEXT (PRETreatment EXTent of disease) approach.^7,14 Based on comprehensive data from 1605 children participating in multicenter trials, the CHIC risk stratification defines and provides risk trees for very low-, low-, intermediate-, and high-risk groups. The most important predictors included AFP levels, patient age, extent of disease in the liver (particularly involving major hepatic veins), and the presence of metastases.

Further improvements to the diagnosis and staging of hepatoblastoma are credited to consensus-based recommendations for imaging that were created in the context of the PRETEXT staging system.¹³ While ultrasound is recommended for the initial approach to diagnosis, this consensus calls for MRI with hepatobiliary contrast to better characterize the lesion and detect satellite lesions. This form of imaging is also recommended for follow-up after treatment, but results should be interpreted in the context of biomarkers, such as AFP levels, pathologic grading, and tumor subtypes.

In patients with the most common familial disorders associated with a predisposition for hepatoblastoma, such as adenomatous polyposis, Beckwith-Weidemann spectrum, or trisomy 18, regular surveillance for hepatoblastoma is recommended during the early years of life.⁸ Characterization of the genetic and molecular features of patients who present with hepatoblastoma might be useful in determining prognosis. Of genetic features, mutations in the CTNNB1 gene are the most common, but several genes in the Wnt pathway are also linked to hepatoblastoma formation.⁹

Along with the progress in subtyping patients by genetics, epigenetics, and molecular features, there is a growing appreciation for the heterogeneity of hepatoblastoma and the likelihood that treatment strategies can be better individualized to improve outcomes in high-risk patients. This progress is expected to accelerate further when results from the results from the Pediatric Hepatic International Tumor Trial (PHITT) are published. These data are expected to be available in 2025, and may help with prognostication and understanding the biology of hepatoblastoma in relation to outcomes.

Treatment Strategies in Hepatoblastoma
For low-grade hepatoblastoma, the first-line therapy is surgery, which can be sufficient for cure without relapse in selected patients with PRETEXT group 1 disease. Although only 40% to 60% of patients have resectable disease at diagnosis,¹⁰ there are several strategies to shrink tumor bulk, particularly chemotherapy due to the relatively high sensitivity of hepatoblastoma to cytotoxic therapies. The intensity of chemotherapy is increased relative to risk.¹¹ For example, cisplatin-based regimens are considered for low-risk patients, while additional therapies, such as doxorubicin, irinotecan, or both, are added in patients at higher risk. Cure is common if these regimens permit a margin-free resection, although relapse does occur in a subset of patients.

If adequate debulking of the tumor cannot be achieved with conventional surgery, liver transplantation is typically offered for patients without extrahepatic disease or after distant metastases have been successfully excised. With liver transplantation and combination therapies to inhibit relapse associated with seeding, long-term survival rates of 80% have been reported.³ Judicious use of transplantation in patients with high-risk disease that raises the potential for relapse has been credited with rates of long-term survival that exceed 80% in some series. However, there is concern of offering transplantation when it is not necessary. In patients who are high risk with multiple lesions in the liver, there is a general agreement that transplantation reduces the likelihood of subsequent relapse; however, as the precision of aggressive resection coupled with effective chemotherapy has improved, there are more patients in whom the optimal choice might not be debated by experts.

Review articles typically cite the likelihood of an overall 5-year survival in patients with hepatoblastoma as being on the order of 80%.¹ This rate includes children with late-onset disease, which is generally associated with a worse prognosis, and patients who eventually experience disease relapse. Survival rates are now likely to be substantially higher, with progress developing better treatment protocols for both groups. In the absence of high-risk features, long-term survival rates of 90% or higher are now being reported in some centers with high relative volumes of hepatoblastoma, regardless of baseline risks. 

PHITT
The rarity of hepatoblastoma poses a significant challenge to conducting prospective studies with sufficient sample sizes to evaluate the overall efficacy of treatments and their effectiveness in patient subgroups based on specific clinical characteristics and disease severity. PHITT is the first international collaborative liver tumors trial to use a consensus approach. Centers in Europe, Japan, and the United States are participating through regional cancer study consortia. The Cincinnati Children’s Hospital and Medical Center, a leader in hepatoblastoma management in the United States, is anchoring this effort for the Children’s Oncology Group. 

In addition to assessing treatment strategies in larger patient cohorts, PHITT is expanding the data available to correlate outcomes across different stages and risk categories based on histological and biological classifications. Hepatoblastoma and hepatocellular carcinoma are being addressed in PHITT, but the design schema for these malignancies differs. For patients enrolled with hepatoblastoma, 4 risk groups have been defined, ranging from very low to high. Within these risk categories, flow charts provide guide selection of treatments based on clinical and disease features.

Cincinnati Children’s Hospital and Medical Center is one of the most active centers for the treatment of hepatoblastoma in the Unites States but manages only 15 to 20 cases of this rare disease per year. PHITT is expected to play a critical role in achieving a high level of valuable data, and the first sets of outcomes from this collaboration are anticipated to be available in early 2025. As the study progresses, meaningful data are expected for the most challenging and some of the rarest hepatoblastoma risk groups.

Summary
The rates of cure are now approaching 100% with surgery and chemotherapy in patients with localized or locally advanced hepatoblastoma. For more advanced, unresectable disease, liver transplantation is effective in most patients, providing high rates of long-term survival. For patients with relapsed disease, advanced treatment protocols at centers with high relative volumes
of hepatoblastoma are now regularly achieving a second remission—many of which are durable. Although prognosis is less favorable in patients who experience a second relapse, long-term survival is achieved even in a proportion of these children. Substantial rates of response and long-term survival have been common in hepatoblastoma diagnosed at early stages, but the recent progress in advanced hepatoblastoma is credited to more aggressive therapies based on a better understanding of the disease characteristics that allows for individualized therapy. There is hope that the larger pool of data becoming available in 2025 from PHITT will prove to be an additional source of information that guides further advances in managing this rare disease.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

How do you assess a patient’s prognosis at the time that they are diagnosed with myelofibrosis?
In the clinic, we use several scoring systems that have been developed based on the outcomes of hundreds of patients with myeloproliferative neoplasms (MPNs) to try to predict survival from time of diagnosis. Disease features associated with a poor prognosis include anemia, elevated white blood cell count, advanced age, constitutional symptoms, and increased peripheral blasts. Some of these scoring systems also incorporate chromosomal abnormalities as well as gene mutations to further refine prognostication.¹

Determining prognosis can be important to creating a treatment plan, particularly to decide if curative allogeneic stem cell transplantation is necessary. However, I always caution patients that these prognostic scoring systems cannot tell the future and that each patient may respond differently to treatment. 

How do you monitor for disease progression?
I will discuss with patients how they are feeling in order to determine if there are any new or developing symptoms that could be a sign that their disease is progressing. I will also review their laboratory work looking for changes in blood counts that could be a signal of disease evolution.

For instance, development of anemia or thrombocytopenia may signal worsening bone marrow function or progression to secondary acute leukemia. If there are concerning signs or symptoms, I will then perform a bone marrow biopsy with aspirate that will include assessment of mutations and chromosomal abnormalities to determine if their disease is progressing.

What are the first-line treatment options for a patient newly diagnosed with myelofibrosis, and how do you determine the best course of action?
For patients with myelofibrosis, the first-line treatment options include Janus kinase (JAK) inhibitors, which are effective at improving spleen size and reducing symptom burden. The US Food and Drug Administration (FDA) has approved 4 JAK inhibitors for the treatment of myelofibrosis: ruxolitinib, fedratinib, pacritinib, and momelotinib (Table).^2-13 In general, ruxolitinib is the first-line treatment option unless there is thrombocytopenia, in which case pacritinib is more appropriate. In patients with baseline anemia, momelotinib may be the best choice.

Table. FDA-Approved JAK Inhibitors for Myelofibrosis^2-13

Although these agents are effective in reducing spleen size and improving symptoms, they do not affect disease progression. Therefore, I also evaluate all patients for allogeneic stem cell transplantation, which is the only curative modality. Appropriate patients are younger than age 75, with a low comorbidity burden and either intermediate-2 or high-risk disease. In addition, patients who do not respond to frontline JAK inhibitors should be considered for this approach. In patients who are transplant candidates, I will concurrently have them evaluated and start the process of finding a donor while initiating a JAK inhibitor.

What are the most common adverse effects of JAK inhibitors, and how do you help patients manage these issues?
There are short- and long-term effects of JAK inhibitors. Focusing on ruxolitinib, the most frequently used JAK inhibitor, patients can experience bruising, dizziness, and headaches, which generally resolves within a few weeks. Notable longer-term adverse events of ruxolitinib include increased rates of shingles infection, so I encourage my patients to get vaccinated for shingles before initiation.¹¹ Weight gain has also been reported with ruxolitinib, but not with other JAK inhibitors.^12,13 The other main adverse effect of ruxolitinib is worsening anemia and thrombocythemia, so I closely monitor blood counts during treatment.

What are some of the key reasons why patients may develop JAK inhibitor resistance or intolerance, and how do you address these problems in clinical practice?
There are a variety of reasons why patients discontinue a JAK inhibitor, but these can be lumped into 2 categories: (1) the medication has not achieved, or is no longer achieving, treatment goals, or (2) adverse effects from the JAK inhibitor require discontinuation. In a large series of patients with myelofibrosis who were treated with ruxolitinib, about 60% of discontinuations were because of JAK inhibitor refractoriness/resistance, and around 40% were from adverse events.¹⁴

Resistance can arise from several mechanisms, including activation of alternative pathways and clonal evolution that are ongoing regardless of JAK inhibition. In clinical practice, we are addressing JAK inhibitor resistance through clinical trials of novel therapies, particularly in combination with JAK inhibitors, which can potentially mitigate resistance. New JAK inhibitors are also being developed that may more effectively target the overactive JAK-signal transducer and activator of transcription (STAT) pathway and reduce resistance.

In terms of intolerance, there are many strategies to address nonhematological toxicities, and with the availability of pacritinib and momelotinib, patients in whom thrombocytopenia and anemia develop can be safely and effectively transitioned to an alternative JAK inhibitor if they experience adverse effects with ruxolitinib.

How do you incorporate patient-reported outcomes or quality-of-life measures into treatment planning?
Symptom assessment is a key component of the care for myelofibrosis. There are several well-validated patient-reported symptom assessment forms for myelofibrosis.¹⁵ These can be helpful both to quantify the burden of myelofibrosis-related symptoms, as well as to track progress of these symptoms over time. I generally incorporate these assessments into the initial evaluation and several times throughout therapy.

However, many symptoms are not captured on these assessments, and so I spend considerable time speaking to patients about how they are feeling and tracking their symptoms carefully over time. I also find it helpful to assess how a patient feels during treatment using the Patient’s Global Impression of Change (PGIC) questionnaire, which is a 7-point scale reflecting overall improvement compared with baseline.

Can you share any strategies for helping patients navigate the emotional and psychological challenges of living with a chronic disease like myelofibrosis?
In my experience, addressing emotional and psychological stress is one of the greatest challenges in caring for patients with myelofibrosis. Myelofibrosis significantly affects a patient’s quality of life and productivity.¹⁶ Some strategies that my patients have found helpful include engaging with the patient community and learning from others who have been living with this disease for years.

Anecdotally, I find that patients who exercise regularly and maintain an active lifestyle benefit psychologically. I have also observed that involving a support system is critical for dealing with the emotional stress of living with a chronic disease. It is particularly helpful if the patient brings a supportive friend or family member to appointments, as they can help the patient process the information discussed.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

How do you assess a patient’s prognosis at the time that they are diagnosed with myelofibrosis?
In the clinic, we use several scoring systems that have been developed based on the outcomes of hundreds of patients with myeloproliferative neoplasms (MPNs) to try to predict survival from time of diagnosis. Disease features associated with a poor prognosis include anemia, elevated white blood cell count, advanced age, constitutional symptoms, and increased peripheral blasts. Some of these scoring systems also incorporate chromosomal abnormalities as well as gene mutations to further refine prognostication.¹

Determining prognosis can be important to creating a treatment plan, particularly to decide if curative allogeneic stem cell transplantation is necessary. However, I always caution patients that these prognostic scoring systems cannot tell the future and that each patient may respond differently to treatment. 

How do you monitor for disease progression?
I will discuss with patients how they are feeling in order to determine if there are any new or developing symptoms that could be a sign that their disease is progressing. I will also review their laboratory work looking for changes in blood counts that could be a signal of disease evolution.

For instance, development of anemia or thrombocytopenia may signal worsening bone marrow function or progression to secondary acute leukemia. If there are concerning signs or symptoms, I will then perform a bone marrow biopsy with aspirate that will include assessment of mutations and chromosomal abnormalities to determine if their disease is progressing.

What are the first-line treatment options for a patient newly diagnosed with myelofibrosis, and how do you determine the best course of action?
For patients with myelofibrosis, the first-line treatment options include Janus kinase (JAK) inhibitors, which are effective at improving spleen size and reducing symptom burden. The US Food and Drug Administration (FDA) has approved 4 JAK inhibitors for the treatment of myelofibrosis: ruxolitinib, fedratinib, pacritinib, and momelotinib (Table).^2-13 In general, ruxolitinib is the first-line treatment option unless there is thrombocytopenia, in which case pacritinib is more appropriate. In patients with baseline anemia, momelotinib may be the best choice.

Table. FDA-Approved JAK Inhibitors for Myelofibrosis^2-13

Although these agents are effective in reducing spleen size and improving symptoms, they do not affect disease progression. Therefore, I also evaluate all patients for allogeneic stem cell transplantation, which is the only curative modality. Appropriate patients are younger than age 75, with a low comorbidity burden and either intermediate-2 or high-risk disease. In addition, patients who do not respond to frontline JAK inhibitors should be considered for this approach. In patients who are transplant candidates, I will concurrently have them evaluated and start the process of finding a donor while initiating a JAK inhibitor.

What are the most common adverse effects of JAK inhibitors, and how do you help patients manage these issues?
There are short- and long-term effects of JAK inhibitors. Focusing on ruxolitinib, the most frequently used JAK inhibitor, patients can experience bruising, dizziness, and headaches, which generally resolves within a few weeks. Notable longer-term adverse events of ruxolitinib include increased rates of shingles infection, so I encourage my patients to get vaccinated for shingles before initiation.¹¹ Weight gain has also been reported with ruxolitinib, but not with other JAK inhibitors.^12,13 The other main adverse effect of ruxolitinib is worsening anemia and thrombocythemia, so I closely monitor blood counts during treatment.

What are some of the key reasons why patients may develop JAK inhibitor resistance or intolerance, and how do you address these problems in clinical practice?
There are a variety of reasons why patients discontinue a JAK inhibitor, but these can be lumped into 2 categories: (1) the medication has not achieved, or is no longer achieving, treatment goals, or (2) adverse effects from the JAK inhibitor require discontinuation. In a large series of patients with myelofibrosis who were treated with ruxolitinib, about 60% of discontinuations were because of JAK inhibitor refractoriness/resistance, and around 40% were from adverse events.¹⁴

Resistance can arise from several mechanisms, including activation of alternative pathways and clonal evolution that are ongoing regardless of JAK inhibition. In clinical practice, we are addressing JAK inhibitor resistance through clinical trials of novel therapies, particularly in combination with JAK inhibitors, which can potentially mitigate resistance. New JAK inhibitors are also being developed that may more effectively target the overactive JAK-signal transducer and activator of transcription (STAT) pathway and reduce resistance.

In terms of intolerance, there are many strategies to address nonhematological toxicities, and with the availability of pacritinib and momelotinib, patients in whom thrombocytopenia and anemia develop can be safely and effectively transitioned to an alternative JAK inhibitor if they experience adverse effects with ruxolitinib.

How do you incorporate patient-reported outcomes or quality-of-life measures into treatment planning?
Symptom assessment is a key component of the care for myelofibrosis. There are several well-validated patient-reported symptom assessment forms for myelofibrosis.¹⁵ These can be helpful both to quantify the burden of myelofibrosis-related symptoms, as well as to track progress of these symptoms over time. I generally incorporate these assessments into the initial evaluation and several times throughout therapy.

However, many symptoms are not captured on these assessments, and so I spend considerable time speaking to patients about how they are feeling and tracking their symptoms carefully over time. I also find it helpful to assess how a patient feels during treatment using the Patient’s Global Impression of Change (PGIC) questionnaire, which is a 7-point scale reflecting overall improvement compared with baseline.

Can you share any strategies for helping patients navigate the emotional and psychological challenges of living with a chronic disease like myelofibrosis?
In my experience, addressing emotional and psychological stress is one of the greatest challenges in caring for patients with myelofibrosis. Myelofibrosis significantly affects a patient’s quality of life and productivity.¹⁶ Some strategies that my patients have found helpful include engaging with the patient community and learning from others who have been living with this disease for years.

Anecdotally, I find that patients who exercise regularly and maintain an active lifestyle benefit psychologically. I have also observed that involving a support system is critical for dealing with the emotional stress of living with a chronic disease. It is particularly helpful if the patient brings a supportive friend or family member to appointments, as they can help the patient process the information discussed.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

How do you assess a patient’s prognosis at the time that they are diagnosed with myelofibrosis?
In the clinic, we use several scoring systems that have been developed based on the outcomes of hundreds of patients with myeloproliferative neoplasms (MPNs) to try to predict survival from time of diagnosis. Disease features associated with a poor prognosis include anemia, elevated white blood cell count, advanced age, constitutional symptoms, and increased peripheral blasts. Some of these scoring systems also incorporate chromosomal abnormalities as well as gene mutations to further refine prognostication.¹

Determining prognosis can be important to creating a treatment plan, particularly to decide if curative allogeneic stem cell transplantation is necessary. However, I always caution patients that these prognostic scoring systems cannot tell the future and that each patient may respond differently to treatment. 

How do you monitor for disease progression?
I will discuss with patients how they are feeling in order to determine if there are any new or developing symptoms that could be a sign that their disease is progressing. I will also review their laboratory work looking for changes in blood counts that could be a signal of disease evolution.

For instance, development of anemia or thrombocytopenia may signal worsening bone marrow function or progression to secondary acute leukemia. If there are concerning signs or symptoms, I will then perform a bone marrow biopsy with aspirate that will include assessment of mutations and chromosomal abnormalities to determine if their disease is progressing.

What are the first-line treatment options for a patient newly diagnosed with myelofibrosis, and how do you determine the best course of action?
For patients with myelofibrosis, the first-line treatment options include Janus kinase (JAK) inhibitors, which are effective at improving spleen size and reducing symptom burden. The US Food and Drug Administration (FDA) has approved 4 JAK inhibitors for the treatment of myelofibrosis: ruxolitinib, fedratinib, pacritinib, and momelotinib (Table).^2-13 In general, ruxolitinib is the first-line treatment option unless there is thrombocytopenia, in which case pacritinib is more appropriate. In patients with baseline anemia, momelotinib may be the best choice.

Table. FDA-Approved JAK Inhibitors for Myelofibrosis^2-13

Although these agents are effective in reducing spleen size and improving symptoms, they do not affect disease progression. Therefore, I also evaluate all patients for allogeneic stem cell transplantation, which is the only curative modality. Appropriate patients are younger than age 75, with a low comorbidity burden and either intermediate-2 or high-risk disease. In addition, patients who do not respond to frontline JAK inhibitors should be considered for this approach. In patients who are transplant candidates, I will concurrently have them evaluated and start the process of finding a donor while initiating a JAK inhibitor.

What are the most common adverse effects of JAK inhibitors, and how do you help patients manage these issues?
There are short- and long-term effects of JAK inhibitors. Focusing on ruxolitinib, the most frequently used JAK inhibitor, patients can experience bruising, dizziness, and headaches, which generally resolves within a few weeks. Notable longer-term adverse events of ruxolitinib include increased rates of shingles infection, so I encourage my patients to get vaccinated for shingles before initiation.¹¹ Weight gain has also been reported with ruxolitinib, but not with other JAK inhibitors.^12,13 The other main adverse effect of ruxolitinib is worsening anemia and thrombocythemia, so I closely monitor blood counts during treatment.

What are some of the key reasons why patients may develop JAK inhibitor resistance or intolerance, and how do you address these problems in clinical practice?
There are a variety of reasons why patients discontinue a JAK inhibitor, but these can be lumped into 2 categories: (1) the medication has not achieved, or is no longer achieving, treatment goals, or (2) adverse effects from the JAK inhibitor require discontinuation. In a large series of patients with myelofibrosis who were treated with ruxolitinib, about 60% of discontinuations were because of JAK inhibitor refractoriness/resistance, and around 40% were from adverse events.¹⁴

Resistance can arise from several mechanisms, including activation of alternative pathways and clonal evolution that are ongoing regardless of JAK inhibition. In clinical practice, we are addressing JAK inhibitor resistance through clinical trials of novel therapies, particularly in combination with JAK inhibitors, which can potentially mitigate resistance. New JAK inhibitors are also being developed that may more effectively target the overactive JAK-signal transducer and activator of transcription (STAT) pathway and reduce resistance.

In terms of intolerance, there are many strategies to address nonhematological toxicities, and with the availability of pacritinib and momelotinib, patients in whom thrombocytopenia and anemia develop can be safely and effectively transitioned to an alternative JAK inhibitor if they experience adverse effects with ruxolitinib.

How do you incorporate patient-reported outcomes or quality-of-life measures into treatment planning?
Symptom assessment is a key component of the care for myelofibrosis. There are several well-validated patient-reported symptom assessment forms for myelofibrosis.¹⁵ These can be helpful both to quantify the burden of myelofibrosis-related symptoms, as well as to track progress of these symptoms over time. I generally incorporate these assessments into the initial evaluation and several times throughout therapy.

However, many symptoms are not captured on these assessments, and so I spend considerable time speaking to patients about how they are feeling and tracking their symptoms carefully over time. I also find it helpful to assess how a patient feels during treatment using the Patient’s Global Impression of Change (PGIC) questionnaire, which is a 7-point scale reflecting overall improvement compared with baseline.

Can you share any strategies for helping patients navigate the emotional and psychological challenges of living with a chronic disease like myelofibrosis?
In my experience, addressing emotional and psychological stress is one of the greatest challenges in caring for patients with myelofibrosis. Myelofibrosis significantly affects a patient’s quality of life and productivity.¹⁶ Some strategies that my patients have found helpful include engaging with the patient community and learning from others who have been living with this disease for years.

Anecdotally, I find that patients who exercise regularly and maintain an active lifestyle benefit psychologically. I have also observed that involving a support system is critical for dealing with the emotional stress of living with a chronic disease. It is particularly helpful if the patient brings a supportive friend or family member to appointments, as they can help the patient process the information discussed.

Read more from the 2024 Rare Diseases Report: Hematology and Oncology.

Posttraumatic stress disorder (PTSD) is the most likely diagnosis given the patient's symptoms — recurrent nightmares, flashbacks, and anxiety triggered by trauma-related noises, all of which are classic indicators of the disorder. His history of witnessing traumatic events at work, including a fatal accident, further reinforces this diagnosis and strongly suggests PTSD as the most fitting explanation. Although the brain scan does not diagnose PTSD directly, it plays an important role in ruling out other potential causes, such as structural brain damage, that could be contributing to his symptoms. Thus, the patient's symptoms are more likely a result of PTSD rather than an underlying organic brain injury.

Although major depressive disorder could explain some of the patient's symptoms, such as impaired daily functioning and withdrawal, the presence of recurrent nightmares, flashbacks, and trauma-specific triggers are more indicative of PTSD.

Generalized anxiety disorder might account for the patient's heightened anxiety, but it typically involves chronic, pervasive worry rather than the trauma-specific symptoms seen here.

Chronic traumatic encephalopathy (CTE) is a possible concern given the patient's occupation and the findings on the CT scan. However, CTE generally presents with cognitive and behavioral changes over time, such as memory loss and aggression, rather than the distinctive trauma-related symptoms characteristic of PTSD.

Individuals with PTSD often display heightened emotional, cognitive, and behavioral responses when exposed to trauma-related cues; these responses include severe anxiety, dissociative episodes, flashbacks, and heightened reactivity. To manage their increased arousal, individuals with PTSD frequently engage in avoidance behaviors, which can result in emotional numbing, diminished interest in daily activities, and, in more severe cases, social withdrawal.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), the diagnostic criteria for PTSD in individuals older than 6 years include (A) exposure to actual or threatened death, serious injury, or sexual violence; (B) the presence of one or more intrusion symptoms related to the trauma; (C) persistent avoidance of trauma-related stimuli; (D) negative changes in cognition and mood associated with the trauma; and (E) marked alterations in arousal and reactivity, with at least two specific symptoms.

Trauma-focused psychotherapy is generally recommended as the first-line treatment for most adults with PTSD, with exposure-based therapies often preferred over other therapeutic approaches or pharmacologic treatments, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors. However, in patients with comorbid conditions such as depression or psychosis that hinder their ability to engage in trauma-focused therapy, initial pharmacologic management is recommended until symptoms stabilize, allowing for the later introduction of psychotherapy. Clinical trials and meta-analyses have demonstrated the effectiveness of various trauma-focused therapies, including trauma-focused cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing. Treatment selection should be made collaboratively, considering the patient's presentation and preferences and the therapist's expertise.

For effective management of PTSD, medication regimens should be maintained for at least 6 months to 1 year to prevent relapse or recurrence. Multiple clinical trials have shown that patients who continue SSRIs after acute treatment are less likely to experience a relapse than those who switch to placebo.

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Posttraumatic stress disorder (PTSD) is the most likely diagnosis given the patient's symptoms — recurrent nightmares, flashbacks, and anxiety triggered by trauma-related noises, all of which are classic indicators of the disorder. His history of witnessing traumatic events at work, including a fatal accident, further reinforces this diagnosis and strongly suggests PTSD as the most fitting explanation. Although the brain scan does not diagnose PTSD directly, it plays an important role in ruling out other potential causes, such as structural brain damage, that could be contributing to his symptoms. Thus, the patient's symptoms are more likely a result of PTSD rather than an underlying organic brain injury.

Although major depressive disorder could explain some of the patient's symptoms, such as impaired daily functioning and withdrawal, the presence of recurrent nightmares, flashbacks, and trauma-specific triggers are more indicative of PTSD.

Generalized anxiety disorder might account for the patient's heightened anxiety, but it typically involves chronic, pervasive worry rather than the trauma-specific symptoms seen here.

Chronic traumatic encephalopathy (CTE) is a possible concern given the patient's occupation and the findings on the CT scan. However, CTE generally presents with cognitive and behavioral changes over time, such as memory loss and aggression, rather than the distinctive trauma-related symptoms characteristic of PTSD.

Individuals with PTSD often display heightened emotional, cognitive, and behavioral responses when exposed to trauma-related cues; these responses include severe anxiety, dissociative episodes, flashbacks, and heightened reactivity. To manage their increased arousal, individuals with PTSD frequently engage in avoidance behaviors, which can result in emotional numbing, diminished interest in daily activities, and, in more severe cases, social withdrawal.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), the diagnostic criteria for PTSD in individuals older than 6 years include (A) exposure to actual or threatened death, serious injury, or sexual violence; (B) the presence of one or more intrusion symptoms related to the trauma; (C) persistent avoidance of trauma-related stimuli; (D) negative changes in cognition and mood associated with the trauma; and (E) marked alterations in arousal and reactivity, with at least two specific symptoms.

Trauma-focused psychotherapy is generally recommended as the first-line treatment for most adults with PTSD, with exposure-based therapies often preferred over other therapeutic approaches or pharmacologic treatments, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors. However, in patients with comorbid conditions such as depression or psychosis that hinder their ability to engage in trauma-focused therapy, initial pharmacologic management is recommended until symptoms stabilize, allowing for the later introduction of psychotherapy. Clinical trials and meta-analyses have demonstrated the effectiveness of various trauma-focused therapies, including trauma-focused cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing. Treatment selection should be made collaboratively, considering the patient's presentation and preferences and the therapist's expertise.

For effective management of PTSD, medication regimens should be maintained for at least 6 months to 1 year to prevent relapse or recurrence. Multiple clinical trials have shown that patients who continue SSRIs after acute treatment are less likely to experience a relapse than those who switch to placebo.

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Posttraumatic stress disorder (PTSD) is the most likely diagnosis given the patient's symptoms — recurrent nightmares, flashbacks, and anxiety triggered by trauma-related noises, all of which are classic indicators of the disorder. His history of witnessing traumatic events at work, including a fatal accident, further reinforces this diagnosis and strongly suggests PTSD as the most fitting explanation. Although the brain scan does not diagnose PTSD directly, it plays an important role in ruling out other potential causes, such as structural brain damage, that could be contributing to his symptoms. Thus, the patient's symptoms are more likely a result of PTSD rather than an underlying organic brain injury.

Although major depressive disorder could explain some of the patient's symptoms, such as impaired daily functioning and withdrawal, the presence of recurrent nightmares, flashbacks, and trauma-specific triggers are more indicative of PTSD.

Generalized anxiety disorder might account for the patient's heightened anxiety, but it typically involves chronic, pervasive worry rather than the trauma-specific symptoms seen here.

Chronic traumatic encephalopathy (CTE) is a possible concern given the patient's occupation and the findings on the CT scan. However, CTE generally presents with cognitive and behavioral changes over time, such as memory loss and aggression, rather than the distinctive trauma-related symptoms characteristic of PTSD.

Individuals with PTSD often display heightened emotional, cognitive, and behavioral responses when exposed to trauma-related cues; these responses include severe anxiety, dissociative episodes, flashbacks, and heightened reactivity. To manage their increased arousal, individuals with PTSD frequently engage in avoidance behaviors, which can result in emotional numbing, diminished interest in daily activities, and, in more severe cases, social withdrawal.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), the diagnostic criteria for PTSD in individuals older than 6 years include (A) exposure to actual or threatened death, serious injury, or sexual violence; (B) the presence of one or more intrusion symptoms related to the trauma; (C) persistent avoidance of trauma-related stimuli; (D) negative changes in cognition and mood associated with the trauma; and (E) marked alterations in arousal and reactivity, with at least two specific symptoms.

Trauma-focused psychotherapy is generally recommended as the first-line treatment for most adults with PTSD, with exposure-based therapies often preferred over other therapeutic approaches or pharmacologic treatments, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors. However, in patients with comorbid conditions such as depression or psychosis that hinder their ability to engage in trauma-focused therapy, initial pharmacologic management is recommended until symptoms stabilize, allowing for the later introduction of psychotherapy. Clinical trials and meta-analyses have demonstrated the effectiveness of various trauma-focused therapies, including trauma-focused cognitive-behavioral therapy, prolonged exposure therapy, and eye movement desensitization and reprocessing. Treatment selection should be made collaboratively, considering the patient's presentation and preferences and the therapist's expertise.

For effective management of PTSD, medication regimens should be maintained for at least 6 months to 1 year to prevent relapse or recurrence. Multiple clinical trials have shown that patients who continue SSRIs after acute treatment are less likely to experience a relapse than those who switch to placebo.

Heidi Moawad, MD, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Heidi Moawad, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

Editor's Note: This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Editor's Note: This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Editor's Note: This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

Acute agranulocytosis and aseptic meningitis are serious adverse effects (AEs) associated with sulfamethoxazole-trimethoprim. Acute agranulocytosis is a rare, potentially life-threatening blood dyscrasia characterized by a neutrophil count of < 500 cells per μL, with no relevant decrease in hemoglobin or platelet levels.¹ Patients with agranulocytosis may be asymptomatic or experience severe sore throat, pharyngitis, or tonsillitis in combination with high fever, rigors, headaches, or malaise. These AEs are commonly classified as idiosyncratic and, in most cases, attributable to medications. If drug-induced agranulocytosis is suspected, the patient should discontinue the medication immediately.¹

Meningitis is an inflammatory disease typically caused by viral or bacterial infections; however, it may also be attributed to medications or malignancy. Inflammation of the meninges with a negative bacterial cerebrospinal fluid culture is classified as aseptic meningitis. Distinguishing between aseptic and bacterial meningitis is crucial due to differences in illness severity, treatment options, and prognosis.² Symptoms of meningitis may include fever, headache, nuchal rigidity, nausea, or vomiting.³ Several classes of medications can cause drug-induced aseptic meningitis (DIAM), but the most commonly reported antibiotic is sulfamethoxazole-trimethoprim.

DIAM is more prevalent in immunocompromised patients, such as those with a history of HIV/AIDS, organ transplant, collagen vascular disease, or malignancy, who may be prescribed sulfamethoxazoletrimethoprim for prophylaxis or treatment of infection.² The case described in this article serves as a distinctive example of acute agranulocytosis complicated with aseptic meningitis caused by sulfamethoxazole-trimethoprim in an immunocompetent patient.

Case Presentation

A healthy male veteran aged 39 years presented to the Fargo Veterans Affairs Medical Center emergency department (ED) for worsening left testicular pain and increased urinary urgency and frequency for about 48 hours. The patient had no known medication allergies, was current on vaccinations, and his only relevant prescription was valacyclovir for herpes labialis. The evaluation included urinalysis, blood tests, and scrotal ultrasound. The urinalysis, blood tests, and vitals were unremarkable for any signs of systemic infection. The scrotal ultrasound was significant for left focal area of abnormal echogenicity with absent blood flow in the superior left testicle and a significant increase in blood flow around the left epididymis. Mild swelling in the left epididymis was present, with no significant testicular or scrotal swelling or skin changes observed. Urology was consulted and prescribed oral sulfamethoxazole-trimethoprim 800-160 mg every 12 hours for 30 days for the treatment of left epididymo-orchitis.

The patient returned to the ED 2 weeks later with fever, chills, headache, generalized body aches, urinary retention, loose stools, and nonspecific chest pressure. A serum blood test revealed significant neutropenia and leukopenia. The patient was admitted for observation, and sulfamethoxazole-trimethoprim was discontinued. The patient received sodium chloride intravenous (IV) fluid, oral potassium chloride supplementation, IV ondansetron, and analgesics, including oral acetaminophen, oral ibuprofen, and IV hydromorphone as needed. Repeated laboratory tests were completed with no specific findings; serum laboratory work, urinalysis, chest and abdominal X-rays, and echocardiogram were all unremarkable. The patient’s neutrophil count dropped from 5100 cells/µL at the initial ED presentation to 900 cells/µL (reference range, 1500-8000 cells/µL) (Table 1). Agranulocytosis quickly resolved after antibiotic discontinuation.

Upon further investigation, the patient took the prescribed sulfamethoxazole-trimethoprim for 10 days before stopping due to the resolution of testicular pain and epididymal swelling. The patient reported initial AEs of loose stools and generalized myalgias when first taking the medication. The patient restarted the antibiotic to complete the course of therapy after not taking it for 2 days. Within 20 minutes of restarting the medication, he experienced myalgias with pruritus, prompting him to return to the ED. Agranulocytosis and aseptic meningitis developed within 12 days after he was prescribed sulfamethoxazole-trimethoprim, though the exact timeframe is unknown.

The patient’s symptoms, except for a persistent headache, resolved during hospitalization. Infectious disease was consulted, and a lumbar puncture was performed due to prior fever and ongoing headaches to rule out a treatable cause of meningitis. The lumbar puncture showed clear spinal fluid, an elevated white blood cell count with neutrophil predominance, and normal protein and glucose levels. Cultures showed no aerobic, anaerobic, or fungal organisms. Herpes virus simplex and Lyme disease testing was not completed during hospitalization. Respiratory panel, legionella, and hepatitis A, B, and C tests were negative (Table 2). The negative laboratory test results strengthened the suspicion of aseptic meningitis caused by sulfamethoxazole-trimethoprim. The neurology consult recommended no additional treatments or tests.

The patient spontaneously recovered 2 days later, with a normalized complete blood count and resolution of headache. Repeat scrotal ultrasounds showed resolution of the left testicle findings. The patient was discharged and seen for a follow-up 14 days later. The final diagnosis requiring hospitalization was aseptic meningitis secondary to a sulfamethoxazole-trimethoprim.

Discussion

Sulfamethoxazole-trimethoprim is a commonly prescribed antibiotic for urinary tract infections, pneumocystis pneumonia, pneumocystis pneumonia prophylaxis, and methicillin-resistant Staphylococcus aureus skin and soft tissue infections. Empiric antibiotics for epididymo-orchitis caused by enteric organisms include levofloxacin or ofloxacin; however sulfamethoxazole-trimethoprim may be considered as alternative.^5,6 Agranulocytosis induced by sulfamethoxazole-trimethoprim may occur due to the inhibition on folic acid metabolism, which makes the highly proliferating cells of the hematopoietic system more susceptible to neutropenia. Agranulocytosis typically occurs within 7 days of treatment initiation and generally resolves within a month after discontinuation of the offending agent.⁷ In this case, agranulocytosis resolved overnight, resulting in leukocytosis. One explanation for the rapid increase in white blood cell count may be the concurrent diagnosis of aseptic meningitis. Alternatively, the patient’s health and immunocompetence may have helped generate an adequate immune response. Medication-induced agranulocytosis is often a diagnosis of exclusion because it is typically difficult to diagnose.⁷ In more severe or complicated cases of agranulocytosis, filgrastim may be indicated.¹

Sulfamethoxazole-trimethoprim is a lipophilic small-molecule medication that can cross the blood-brain barrier and penetrate the tissues of the bone, prostate, and central nervous system.⁸ Specifically, the medication can pass into the cerebrospinal fluid regardless of meningeal inflammation.⁹ The exact mechanism for aseptic meningitis caused by sulfamethoxazole-trimethoprim is unknown; however, it may accumulate in the choroid plexus, causing destructive inflammation of small blood vessels and resulting in aseptic meningitis.¹⁰ The onset of aseptic meningitis can vary from 10 minutes to 10 days after initiation of the medication. Pre-exposure to the medication typically results in earlier onset of symptoms, though patients do not need to have previously taken the medication to develop aseptic meningitis. Patients generally become afebrile with resolution of headache and mental status changes within 48 to 72 hours after stopping the medication or after about 5 to 7 half-lives of the medication are eliminated.¹¹ Some patients may continue to experience worsening symptoms after discontinuation because the medication is already absorbed into the serum and tissues.

DIAM is an uncommon drug-induced hypersensitivity AE of the central nervous system. Diagnosing aseptic meningitis caused by sulfamethoxazole-trimethoprim can be challenging, as antibiotics are given to treat suspected infections, and the symptoms of aseptic meningitis can be hard to differentiate from those of infectious meningitis.¹¹ Close monitoring between the initiation of the medication and the onset of clinical symptoms is necessary to assist in distinguishing between aseptic and infectious meningitis.³ If the causative agent is not discontinued, symptoms can quickly worsen, progressing from fever and headache to confusion, coma, and respiratory depression. A DIAM diagnosis can only be made with resolution of aseptic meningitis after stopping the contributory agent. If appropriate, this can be proven by rechallenging the medication in a controlled setting. The usual treatment for aseptic meningitis is supportive care, including hydration, antiemetics, electrolyte supplementation, and adequate analgesia.³

Differential diagnoses in this case included viral infection, meningitis, and allergic reaction to sulfamethoxazole-trimethoprim. The patient reported history of experiencing symptoms after restarting his antibiotic, raising strong suspicion for DIAM. Initiation of this antibiotic was the only recent medication change noted. Laboratory testing for infectious agents yielded negative results, including tests for aerobic and anaerobic bacteria as well as viral and fungal infections. A lumbar puncture and cerebrospinal fluid culture was clear, with no organisms shown on gram stain. Bacterial or viral meningitis was presumed less likely due to the duration of symptoms, correlation of symptoms coinciding with restarting the antibiotic, and negative cerebrospinal fluid culture results.

It was concluded that agranulocytosis and aseptic meningitis were likely induced by sulfamethoxazole-trimethoprim as supported by the improvement upon discontinuing the medication and subsequent worsening upon restarting it. Concurrent agranulocytosis and aseptic meningitis is rare, and there is typically no correlation between the 2 reactions. Since agranulocytosis may be asymptomatic, this case highlights the need to monitor blood cell counts in patients using sulfamethoxazole-trimethoprim. The possibility of DIAM should be considered in patients presenting with flu-like symptoms, and a lumbar puncture may be collected to rule out aseptic meningitis if the patient’s AEs are severe following the initiation of an antibiotic, particularly in immunosuppressed patients taking sulfamethoxazole-trimethoprim. This case is unusual because the patient was healthy and immunocompetent.

This case may not be generalizable and may be difficult to compare to other cases. Every case has patient-specific factors affecting subjective information, including the patient’s baseline, severity of symptoms, and treatment options. This report was based on a single patient case and corresponding results may be found in similar patient cases.

Conclusions

This case emphasizes the rare but serious AEs of acute agranulocytosis complicated with aseptic meningitis after prescribed sulfamethoxazole-trimethoprim. This is a unique case of an immunocompetent patient developing both agranulocytosis and aseptic meningitis after restarting the antibiotic to complete therapy. This case highlights the importance of monitoring blood cell counts and monitoring for signs and symptoms of aseptic meningitis, even during short courses of therapy. Further research is needed to recognize characteristics that may increase the risk for these AEs and to develop strategies for their prevention.

Acute agranulocytosis and aseptic meningitis are serious adverse effects (AEs) associated with sulfamethoxazole-trimethoprim. Acute agranulocytosis is a rare, potentially life-threatening blood dyscrasia characterized by a neutrophil count of < 500 cells per μL, with no relevant decrease in hemoglobin or platelet levels.¹ Patients with agranulocytosis may be asymptomatic or experience severe sore throat, pharyngitis, or tonsillitis in combination with high fever, rigors, headaches, or malaise. These AEs are commonly classified as idiosyncratic and, in most cases, attributable to medications. If drug-induced agranulocytosis is suspected, the patient should discontinue the medication immediately.¹

Meningitis is an inflammatory disease typically caused by viral or bacterial infections; however, it may also be attributed to medications or malignancy. Inflammation of the meninges with a negative bacterial cerebrospinal fluid culture is classified as aseptic meningitis. Distinguishing between aseptic and bacterial meningitis is crucial due to differences in illness severity, treatment options, and prognosis.² Symptoms of meningitis may include fever, headache, nuchal rigidity, nausea, or vomiting.³ Several classes of medications can cause drug-induced aseptic meningitis (DIAM), but the most commonly reported antibiotic is sulfamethoxazole-trimethoprim.

DIAM is more prevalent in immunocompromised patients, such as those with a history of HIV/AIDS, organ transplant, collagen vascular disease, or malignancy, who may be prescribed sulfamethoxazoletrimethoprim for prophylaxis or treatment of infection.² The case described in this article serves as a distinctive example of acute agranulocytosis complicated with aseptic meningitis caused by sulfamethoxazole-trimethoprim in an immunocompetent patient.

Case Presentation

A healthy male veteran aged 39 years presented to the Fargo Veterans Affairs Medical Center emergency department (ED) for worsening left testicular pain and increased urinary urgency and frequency for about 48 hours. The patient had no known medication allergies, was current on vaccinations, and his only relevant prescription was valacyclovir for herpes labialis. The evaluation included urinalysis, blood tests, and scrotal ultrasound. The urinalysis, blood tests, and vitals were unremarkable for any signs of systemic infection. The scrotal ultrasound was significant for left focal area of abnormal echogenicity with absent blood flow in the superior left testicle and a significant increase in blood flow around the left epididymis. Mild swelling in the left epididymis was present, with no significant testicular or scrotal swelling or skin changes observed. Urology was consulted and prescribed oral sulfamethoxazole-trimethoprim 800-160 mg every 12 hours for 30 days for the treatment of left epididymo-orchitis.

The patient returned to the ED 2 weeks later with fever, chills, headache, generalized body aches, urinary retention, loose stools, and nonspecific chest pressure. A serum blood test revealed significant neutropenia and leukopenia. The patient was admitted for observation, and sulfamethoxazole-trimethoprim was discontinued. The patient received sodium chloride intravenous (IV) fluid, oral potassium chloride supplementation, IV ondansetron, and analgesics, including oral acetaminophen, oral ibuprofen, and IV hydromorphone as needed. Repeated laboratory tests were completed with no specific findings; serum laboratory work, urinalysis, chest and abdominal X-rays, and echocardiogram were all unremarkable. The patient’s neutrophil count dropped from 5100 cells/µL at the initial ED presentation to 900 cells/µL (reference range, 1500-8000 cells/µL) (Table 1). Agranulocytosis quickly resolved after antibiotic discontinuation.

Upon further investigation, the patient took the prescribed sulfamethoxazole-trimethoprim for 10 days before stopping due to the resolution of testicular pain and epididymal swelling. The patient reported initial AEs of loose stools and generalized myalgias when first taking the medication. The patient restarted the antibiotic to complete the course of therapy after not taking it for 2 days. Within 20 minutes of restarting the medication, he experienced myalgias with pruritus, prompting him to return to the ED. Agranulocytosis and aseptic meningitis developed within 12 days after he was prescribed sulfamethoxazole-trimethoprim, though the exact timeframe is unknown.

The patient’s symptoms, except for a persistent headache, resolved during hospitalization. Infectious disease was consulted, and a lumbar puncture was performed due to prior fever and ongoing headaches to rule out a treatable cause of meningitis. The lumbar puncture showed clear spinal fluid, an elevated white blood cell count with neutrophil predominance, and normal protein and glucose levels. Cultures showed no aerobic, anaerobic, or fungal organisms. Herpes virus simplex and Lyme disease testing was not completed during hospitalization. Respiratory panel, legionella, and hepatitis A, B, and C tests were negative (Table 2). The negative laboratory test results strengthened the suspicion of aseptic meningitis caused by sulfamethoxazole-trimethoprim. The neurology consult recommended no additional treatments or tests.

The patient spontaneously recovered 2 days later, with a normalized complete blood count and resolution of headache. Repeat scrotal ultrasounds showed resolution of the left testicle findings. The patient was discharged and seen for a follow-up 14 days later. The final diagnosis requiring hospitalization was aseptic meningitis secondary to a sulfamethoxazole-trimethoprim.

Discussion

Sulfamethoxazole-trimethoprim is a commonly prescribed antibiotic for urinary tract infections, pneumocystis pneumonia, pneumocystis pneumonia prophylaxis, and methicillin-resistant Staphylococcus aureus skin and soft tissue infections. Empiric antibiotics for epididymo-orchitis caused by enteric organisms include levofloxacin or ofloxacin; however sulfamethoxazole-trimethoprim may be considered as alternative.^5,6 Agranulocytosis induced by sulfamethoxazole-trimethoprim may occur due to the inhibition on folic acid metabolism, which makes the highly proliferating cells of the hematopoietic system more susceptible to neutropenia. Agranulocytosis typically occurs within 7 days of treatment initiation and generally resolves within a month after discontinuation of the offending agent.⁷ In this case, agranulocytosis resolved overnight, resulting in leukocytosis. One explanation for the rapid increase in white blood cell count may be the concurrent diagnosis of aseptic meningitis. Alternatively, the patient’s health and immunocompetence may have helped generate an adequate immune response. Medication-induced agranulocytosis is often a diagnosis of exclusion because it is typically difficult to diagnose.⁷ In more severe or complicated cases of agranulocytosis, filgrastim may be indicated.¹

Sulfamethoxazole-trimethoprim is a lipophilic small-molecule medication that can cross the blood-brain barrier and penetrate the tissues of the bone, prostate, and central nervous system.⁸ Specifically, the medication can pass into the cerebrospinal fluid regardless of meningeal inflammation.⁹ The exact mechanism for aseptic meningitis caused by sulfamethoxazole-trimethoprim is unknown; however, it may accumulate in the choroid plexus, causing destructive inflammation of small blood vessels and resulting in aseptic meningitis.¹⁰ The onset of aseptic meningitis can vary from 10 minutes to 10 days after initiation of the medication. Pre-exposure to the medication typically results in earlier onset of symptoms, though patients do not need to have previously taken the medication to develop aseptic meningitis. Patients generally become afebrile with resolution of headache and mental status changes within 48 to 72 hours after stopping the medication or after about 5 to 7 half-lives of the medication are eliminated.¹¹ Some patients may continue to experience worsening symptoms after discontinuation because the medication is already absorbed into the serum and tissues.

DIAM is an uncommon drug-induced hypersensitivity AE of the central nervous system. Diagnosing aseptic meningitis caused by sulfamethoxazole-trimethoprim can be challenging, as antibiotics are given to treat suspected infections, and the symptoms of aseptic meningitis can be hard to differentiate from those of infectious meningitis.¹¹ Close monitoring between the initiation of the medication and the onset of clinical symptoms is necessary to assist in distinguishing between aseptic and infectious meningitis.³ If the causative agent is not discontinued, symptoms can quickly worsen, progressing from fever and headache to confusion, coma, and respiratory depression. A DIAM diagnosis can only be made with resolution of aseptic meningitis after stopping the contributory agent. If appropriate, this can be proven by rechallenging the medication in a controlled setting. The usual treatment for aseptic meningitis is supportive care, including hydration, antiemetics, electrolyte supplementation, and adequate analgesia.³

Differential diagnoses in this case included viral infection, meningitis, and allergic reaction to sulfamethoxazole-trimethoprim. The patient reported history of experiencing symptoms after restarting his antibiotic, raising strong suspicion for DIAM. Initiation of this antibiotic was the only recent medication change noted. Laboratory testing for infectious agents yielded negative results, including tests for aerobic and anaerobic bacteria as well as viral and fungal infections. A lumbar puncture and cerebrospinal fluid culture was clear, with no organisms shown on gram stain. Bacterial or viral meningitis was presumed less likely due to the duration of symptoms, correlation of symptoms coinciding with restarting the antibiotic, and negative cerebrospinal fluid culture results.

It was concluded that agranulocytosis and aseptic meningitis were likely induced by sulfamethoxazole-trimethoprim as supported by the improvement upon discontinuing the medication and subsequent worsening upon restarting it. Concurrent agranulocytosis and aseptic meningitis is rare, and there is typically no correlation between the 2 reactions. Since agranulocytosis may be asymptomatic, this case highlights the need to monitor blood cell counts in patients using sulfamethoxazole-trimethoprim. The possibility of DIAM should be considered in patients presenting with flu-like symptoms, and a lumbar puncture may be collected to rule out aseptic meningitis if the patient’s AEs are severe following the initiation of an antibiotic, particularly in immunosuppressed patients taking sulfamethoxazole-trimethoprim. This case is unusual because the patient was healthy and immunocompetent.

This case may not be generalizable and may be difficult to compare to other cases. Every case has patient-specific factors affecting subjective information, including the patient’s baseline, severity of symptoms, and treatment options. This report was based on a single patient case and corresponding results may be found in similar patient cases.

Conclusions

This case emphasizes the rare but serious AEs of acute agranulocytosis complicated with aseptic meningitis after prescribed sulfamethoxazole-trimethoprim. This is a unique case of an immunocompetent patient developing both agranulocytosis and aseptic meningitis after restarting the antibiotic to complete therapy. This case highlights the importance of monitoring blood cell counts and monitoring for signs and symptoms of aseptic meningitis, even during short courses of therapy. Further research is needed to recognize characteristics that may increase the risk for these AEs and to develop strategies for their prevention.

Acute agranulocytosis and aseptic meningitis are serious adverse effects (AEs) associated with sulfamethoxazole-trimethoprim. Acute agranulocytosis is a rare, potentially life-threatening blood dyscrasia characterized by a neutrophil count of < 500 cells per μL, with no relevant decrease in hemoglobin or platelet levels.¹ Patients with agranulocytosis may be asymptomatic or experience severe sore throat, pharyngitis, or tonsillitis in combination with high fever, rigors, headaches, or malaise. These AEs are commonly classified as idiosyncratic and, in most cases, attributable to medications. If drug-induced agranulocytosis is suspected, the patient should discontinue the medication immediately.¹

Meningitis is an inflammatory disease typically caused by viral or bacterial infections; however, it may also be attributed to medications or malignancy. Inflammation of the meninges with a negative bacterial cerebrospinal fluid culture is classified as aseptic meningitis. Distinguishing between aseptic and bacterial meningitis is crucial due to differences in illness severity, treatment options, and prognosis.² Symptoms of meningitis may include fever, headache, nuchal rigidity, nausea, or vomiting.³ Several classes of medications can cause drug-induced aseptic meningitis (DIAM), but the most commonly reported antibiotic is sulfamethoxazole-trimethoprim.

DIAM is more prevalent in immunocompromised patients, such as those with a history of HIV/AIDS, organ transplant, collagen vascular disease, or malignancy, who may be prescribed sulfamethoxazoletrimethoprim for prophylaxis or treatment of infection.² The case described in this article serves as a distinctive example of acute agranulocytosis complicated with aseptic meningitis caused by sulfamethoxazole-trimethoprim in an immunocompetent patient.

Case Presentation

A healthy male veteran aged 39 years presented to the Fargo Veterans Affairs Medical Center emergency department (ED) for worsening left testicular pain and increased urinary urgency and frequency for about 48 hours. The patient had no known medication allergies, was current on vaccinations, and his only relevant prescription was valacyclovir for herpes labialis. The evaluation included urinalysis, blood tests, and scrotal ultrasound. The urinalysis, blood tests, and vitals were unremarkable for any signs of systemic infection. The scrotal ultrasound was significant for left focal area of abnormal echogenicity with absent blood flow in the superior left testicle and a significant increase in blood flow around the left epididymis. Mild swelling in the left epididymis was present, with no significant testicular or scrotal swelling or skin changes observed. Urology was consulted and prescribed oral sulfamethoxazole-trimethoprim 800-160 mg every 12 hours for 30 days for the treatment of left epididymo-orchitis.

The patient returned to the ED 2 weeks later with fever, chills, headache, generalized body aches, urinary retention, loose stools, and nonspecific chest pressure. A serum blood test revealed significant neutropenia and leukopenia. The patient was admitted for observation, and sulfamethoxazole-trimethoprim was discontinued. The patient received sodium chloride intravenous (IV) fluid, oral potassium chloride supplementation, IV ondansetron, and analgesics, including oral acetaminophen, oral ibuprofen, and IV hydromorphone as needed. Repeated laboratory tests were completed with no specific findings; serum laboratory work, urinalysis, chest and abdominal X-rays, and echocardiogram were all unremarkable. The patient’s neutrophil count dropped from 5100 cells/µL at the initial ED presentation to 900 cells/µL (reference range, 1500-8000 cells/µL) (Table 1). Agranulocytosis quickly resolved after antibiotic discontinuation.

Upon further investigation, the patient took the prescribed sulfamethoxazole-trimethoprim for 10 days before stopping due to the resolution of testicular pain and epididymal swelling. The patient reported initial AEs of loose stools and generalized myalgias when first taking the medication. The patient restarted the antibiotic to complete the course of therapy after not taking it for 2 days. Within 20 minutes of restarting the medication, he experienced myalgias with pruritus, prompting him to return to the ED. Agranulocytosis and aseptic meningitis developed within 12 days after he was prescribed sulfamethoxazole-trimethoprim, though the exact timeframe is unknown.

The patient’s symptoms, except for a persistent headache, resolved during hospitalization. Infectious disease was consulted, and a lumbar puncture was performed due to prior fever and ongoing headaches to rule out a treatable cause of meningitis. The lumbar puncture showed clear spinal fluid, an elevated white blood cell count with neutrophil predominance, and normal protein and glucose levels. Cultures showed no aerobic, anaerobic, or fungal organisms. Herpes virus simplex and Lyme disease testing was not completed during hospitalization. Respiratory panel, legionella, and hepatitis A, B, and C tests were negative (Table 2). The negative laboratory test results strengthened the suspicion of aseptic meningitis caused by sulfamethoxazole-trimethoprim. The neurology consult recommended no additional treatments or tests.

The patient spontaneously recovered 2 days later, with a normalized complete blood count and resolution of headache. Repeat scrotal ultrasounds showed resolution of the left testicle findings. The patient was discharged and seen for a follow-up 14 days later. The final diagnosis requiring hospitalization was aseptic meningitis secondary to a sulfamethoxazole-trimethoprim.

Discussion

Sulfamethoxazole-trimethoprim is a commonly prescribed antibiotic for urinary tract infections, pneumocystis pneumonia, pneumocystis pneumonia prophylaxis, and methicillin-resistant Staphylococcus aureus skin and soft tissue infections. Empiric antibiotics for epididymo-orchitis caused by enteric organisms include levofloxacin or ofloxacin; however sulfamethoxazole-trimethoprim may be considered as alternative.^5,6 Agranulocytosis induced by sulfamethoxazole-trimethoprim may occur due to the inhibition on folic acid metabolism, which makes the highly proliferating cells of the hematopoietic system more susceptible to neutropenia. Agranulocytosis typically occurs within 7 days of treatment initiation and generally resolves within a month after discontinuation of the offending agent.⁷ In this case, agranulocytosis resolved overnight, resulting in leukocytosis. One explanation for the rapid increase in white blood cell count may be the concurrent diagnosis of aseptic meningitis. Alternatively, the patient’s health and immunocompetence may have helped generate an adequate immune response. Medication-induced agranulocytosis is often a diagnosis of exclusion because it is typically difficult to diagnose.⁷ In more severe or complicated cases of agranulocytosis, filgrastim may be indicated.¹

Sulfamethoxazole-trimethoprim is a lipophilic small-molecule medication that can cross the blood-brain barrier and penetrate the tissues of the bone, prostate, and central nervous system.⁸ Specifically, the medication can pass into the cerebrospinal fluid regardless of meningeal inflammation.⁹ The exact mechanism for aseptic meningitis caused by sulfamethoxazole-trimethoprim is unknown; however, it may accumulate in the choroid plexus, causing destructive inflammation of small blood vessels and resulting in aseptic meningitis.¹⁰ The onset of aseptic meningitis can vary from 10 minutes to 10 days after initiation of the medication. Pre-exposure to the medication typically results in earlier onset of symptoms, though patients do not need to have previously taken the medication to develop aseptic meningitis. Patients generally become afebrile with resolution of headache and mental status changes within 48 to 72 hours after stopping the medication or after about 5 to 7 half-lives of the medication are eliminated.¹¹ Some patients may continue to experience worsening symptoms after discontinuation because the medication is already absorbed into the serum and tissues.

DIAM is an uncommon drug-induced hypersensitivity AE of the central nervous system. Diagnosing aseptic meningitis caused by sulfamethoxazole-trimethoprim can be challenging, as antibiotics are given to treat suspected infections, and the symptoms of aseptic meningitis can be hard to differentiate from those of infectious meningitis.¹¹ Close monitoring between the initiation of the medication and the onset of clinical symptoms is necessary to assist in distinguishing between aseptic and infectious meningitis.³ If the causative agent is not discontinued, symptoms can quickly worsen, progressing from fever and headache to confusion, coma, and respiratory depression. A DIAM diagnosis can only be made with resolution of aseptic meningitis after stopping the contributory agent. If appropriate, this can be proven by rechallenging the medication in a controlled setting. The usual treatment for aseptic meningitis is supportive care, including hydration, antiemetics, electrolyte supplementation, and adequate analgesia.³

Differential diagnoses in this case included viral infection, meningitis, and allergic reaction to sulfamethoxazole-trimethoprim. The patient reported history of experiencing symptoms after restarting his antibiotic, raising strong suspicion for DIAM. Initiation of this antibiotic was the only recent medication change noted. Laboratory testing for infectious agents yielded negative results, including tests for aerobic and anaerobic bacteria as well as viral and fungal infections. A lumbar puncture and cerebrospinal fluid culture was clear, with no organisms shown on gram stain. Bacterial or viral meningitis was presumed less likely due to the duration of symptoms, correlation of symptoms coinciding with restarting the antibiotic, and negative cerebrospinal fluid culture results.

It was concluded that agranulocytosis and aseptic meningitis were likely induced by sulfamethoxazole-trimethoprim as supported by the improvement upon discontinuing the medication and subsequent worsening upon restarting it. Concurrent agranulocytosis and aseptic meningitis is rare, and there is typically no correlation between the 2 reactions. Since agranulocytosis may be asymptomatic, this case highlights the need to monitor blood cell counts in patients using sulfamethoxazole-trimethoprim. The possibility of DIAM should be considered in patients presenting with flu-like symptoms, and a lumbar puncture may be collected to rule out aseptic meningitis if the patient’s AEs are severe following the initiation of an antibiotic, particularly in immunosuppressed patients taking sulfamethoxazole-trimethoprim. This case is unusual because the patient was healthy and immunocompetent.

This case may not be generalizable and may be difficult to compare to other cases. Every case has patient-specific factors affecting subjective information, including the patient’s baseline, severity of symptoms, and treatment options. This report was based on a single patient case and corresponding results may be found in similar patient cases.

Conclusions

This case emphasizes the rare but serious AEs of acute agranulocytosis complicated with aseptic meningitis after prescribed sulfamethoxazole-trimethoprim. This is a unique case of an immunocompetent patient developing both agranulocytosis and aseptic meningitis after restarting the antibiotic to complete therapy. This case highlights the importance of monitoring blood cell counts and monitoring for signs and symptoms of aseptic meningitis, even during short courses of therapy. Further research is needed to recognize characteristics that may increase the risk for these AEs and to develop strategies for their prevention.