Rare diseases
Investigational molecules
Locations
Recruiting trials first
4 clinical trials in this condition
Germany
Portugal
FranceGermanyIn short
Activated PI3K delta syndrome (APDS) is a rare condition that weakens the immune system, making it harder for the body to fight infections. Treatment focuses on preventing serious complications, managing symptoms like recurrent infections and enlarged organs, and in some cases, addressing the root cause of the disease through targeted therapies or stem cell transplantation.
When someone receives a diagnosis of Activated PI3K delta syndrome, the main goal of treatment is to help the immune system function better and protect the body from repeated infections that can damage organs over time. Because APDS affects different people in different ways, treatment plans are highly personalized. Some individuals experience mild symptoms that can be managed with supportive care, while others face severe complications requiring more intensive interventions.
The approach to treating APDS depends on several factors, including the person's age, the severity of their symptoms, which organs are affected, and whether complications such as lung damage or lymphoma have developed. Medical teams typically include specialists in immunology (the study of the immune system), infectious diseases, and sometimes hematology or oncology if blood-related complications arise. The treatment landscape has evolved significantly since APDS was first identified in 2013, with new therapies now available that specifically target the molecular problem causing the disease.
Standard treatments have long focused on preventing infections and managing symptoms as they appear. These include replacing missing antibodies, using long-term antibiotics to prevent bacterial infections, and treating viral infections with antiviral medications. However, recent advances in medical research have introduced targeted therapies that address the overactive enzyme responsible for APDS, offering hope for better disease control and improved quality of life. In the most severe cases, when other treatments are not sufficient, doctors may consider hematopoietic stem cell transplantation, which can potentially cure the condition by replacing the faulty immune system with a healthy one.
Immunoglobulin replacement therapy forms the cornerstone of standard APDS treatment. Immunoglobulins are antibodies that healthy immune systems produce naturally to fight infections. People with APDS often have very low levels of certain antibodies, particularly IgG, IgA, and IgE, making them vulnerable to repeated bacterial infections. To compensate for this deficiency, doctors prescribe regular infusions of immunoglobulin, which can be given either intravenously (through a vein) or subcutaneously (under the skin). These infusions typically occur every few weeks and help prevent recurrent respiratory infections, which are among the most common and troublesome symptoms of APDS.
The immunoglobulin used in replacement therapy comes from pooled blood plasma donated by thousands of healthy individuals, providing a broad range of antibodies against many different infections. Most people tolerate these infusions well, though some may experience mild side effects such as headaches, fever, or reactions at the infusion site. The treatment is usually continued indefinitely, as it provides ongoing protection but does not cure the underlying problem. Regular monitoring of antibody levels helps doctors adjust the dose to ensure adequate protection.
Long-term antibiotic prophylaxis represents another important component of standard care. Prophylaxis means taking medication to prevent illness rather than to treat an existing infection. Many individuals with APDS take daily or several-times-weekly antibiotics to reduce the frequency of bacterial respiratory infections. Common choices include medications in the macrolide family or trimethoprim-sulfamethoxazole. The goal is to keep bacteria from establishing infections in the lungs, sinuses, or ears, which can lead to permanent damage if they occur repeatedly.
Similarly, antiviral prophylaxis may be recommended for people who experience recurrent infections with herpes simplex virus or herpes zoster virus (which causes shingles). Medications such as acyclovir or valganciclovir can be taken daily to suppress these viruses and prevent painful outbreaks. Since people with APDS are particularly susceptible to chronic viral infections, including Epstein-Barr virus and cytomegalovirus, antiviral therapy plays an important role in comprehensive care.
When infections do occur despite preventive measures, rapid treatment with appropriate antibiotics or antivirals is essential. Delaying treatment can allow infections to worsen and cause lasting damage, particularly in the lungs. Over time, repeated respiratory infections can lead to a condition called bronchiectasis, where the airways become permanently widened and scarred, making breathing difficult and creating a favorable environment for more infections. Aggressive and early treatment of infections helps prevent this cycle of progressive lung damage.
For individuals who develop autoimmune complications, where the immune system mistakenly attacks the body's own tissues, glucocorticoids (steroid medications) may be prescribed for acute management. Autoimmune problems in APDS can include low blood cell counts (cytopenias), inflammatory bowel disease resembling Crohn's disease, or joint inflammation. Steroids work quickly to reduce inflammation but are typically used for short periods due to their side effects, which can include weight gain, mood changes, elevated blood sugar, and weakened bones with long-term use.
The development of targeted therapies represents one of the most exciting advances in APDS treatment. These medications work by directly addressing the molecular defect that causes the disease rather than just managing its symptoms. Because APDS results from an overactive PI3K delta enzyme, scientists have developed drugs called PI3K delta inhibitors that specifically block this enzyme's excessive activity, helping to normalize immune cell function.
Leniolisib (brand name Joenja) is a selective PI3K delta inhibitor that has been tested in clinical trials and received approval for medical use in the United States in March 2023, making it the first drug specifically approved for APDS. This medication works by reducing the overactive signaling pathway that causes immune cells to function abnormally in people with APDS. In clinical trials, leniolisib demonstrated the ability to reduce enlarged lymph nodes and splenomegaly (enlarged spleen), which are common and troublesome symptoms of the disease. The trials also showed improvements in immune cell counts and function.
Clinical trials of leniolisib included multiple phases, as is standard for new medications. Phase I trials focused on safety, determining what doses could be given without causing unacceptable side effects. Phase II trials examined whether the drug was effective at improving disease symptoms and measured changes in lymph node size, spleen size, and laboratory markers of immune function. Phase III trials compared leniolisib to standard care or placebo to confirm its benefits. The results showed that patients taking leniolisib experienced measurable reductions in lymphoproliferation (abnormal growth of lymphoid tissue) and improvements in some immune parameters.
Leniolisib is recommended as a first-line treatment for individuals with significant lymphoproliferative disease, including problematic lymphadenopathy (swollen lymph nodes) and splenomegaly. The medication is approved for patients aged 12 years and older in the United States. It is taken orally, typically as a daily medication, making it more convenient than infusion therapies. While leniolisib does not cure APDS, it can significantly improve quality of life by reducing symptoms and potentially preventing some complications. In 2025, the medication became available in Europe as well, with the first patient treated at Addenbrooke's Hospital in Cambridge, England.
Like all medications, leniolisib can cause side effects, though not everyone experiences them. Common side effects observed in clinical trials included headaches, upper respiratory tract infections, diarrhea, and nausea. More serious side effects can include infections (since the drug affects immune function), elevated liver enzymes, and rashes. Patients taking leniolisib require regular monitoring with blood tests and check-ups to ensure the medication is working properly and not causing harmful effects. The long-term safety profile is still being studied as more patients use the medication over extended periods.
Sirolimus, also known as rapamycin, is another targeted therapy used off-label for APDS. This medication inhibits a different part of the overactive signaling pathway in APDS cells, specifically targeting mTOR (mammalian target of rapamycin). Sirolimus has been used for many years as an immunosuppressive drug to prevent organ rejection in transplant patients, but researchers discovered it could also help manage lymphoproliferation and immune dysregulation in APDS.
Clinical experience and small studies have shown that sirolimus can reduce enlarged lymph nodes, spleen size, and other lymphoproliferative symptoms in people with APDS. It is typically recommended when leniolisib is unavailable or not suitable for a particular patient. Sirolimus is also taken orally, usually once or twice daily, and requires regular blood monitoring to ensure levels remain in the therapeutic range. Too little medication may not control symptoms, while too much can cause side effects such as mouth sores, increased cholesterol, low blood cell counts, and impaired wound healing. Like leniolisib, sirolimus does not cure APDS but helps control its symptoms.
Both leniolisib and sirolimus represent what doctors call "targeted therapies" because they specifically address the molecular mechanism driving APDS, unlike broad immunosuppressive drugs that affect the entire immune system. This specificity generally means fewer side effects and better disease control. However, these medications are relatively new for APDS treatment, and research continues to determine the optimal timing for starting them, the best doses, and how they affect long-term outcomes.
Clinical trials for APDS have been conducted in multiple countries, including the United States, Europe, and other regions. Eligibility for trials typically requires genetic confirmation of APDS (a variant in either PIK3CD or PIK3R1 genes), documentation of specific symptoms or complications, and absence of certain other health conditions that might interfere with the study. Participation in clinical trials gives patients access to cutting-edge treatments before they become widely available and contributes valuable information that helps improve care for all people with APDS. Families interested in clinical trials can search for opportunities through disease-specific organizations and research registries.
Allogeneic hematopoietic stem cell transplantation (HSCT), sometimes called bone marrow transplant, is reserved for individuals with severe or treatment-refractory APDS. This procedure involves replacing a person's faulty immune system with healthy stem cells from a donor. Unlike other treatments that manage symptoms, HSCT has the potential to cure APDS by providing a new, properly functioning immune system.
The decision to pursue HSCT is complex and requires careful consideration of risks and benefits. The procedure itself carries significant risks, including graft-versus-host disease (where donor immune cells attack the recipient's body), serious infections during the period when the immune system is rebuilding, organ damage from the conditioning regimen (chemotherapy or radiation used to prepare the body for transplant), and potentially death. Because of these risks, HSCT is typically considered only when APDS causes severe, progressive problems that cannot be controlled with other therapies.
Situations that might lead doctors to recommend HSCT include progressive lung damage from recurrent infections despite optimal medical management, recurrent refractory infections that do not respond to antibiotics and immunoglobulin replacement, severe immune dysregulation with life-threatening autoimmune complications, development of lymphoma, or severe organ damage such as liver disease. The timing of transplant is important; performing it before irreversible organ damage occurs generally leads to better outcomes, but not so early that the risks outweigh the benefits.
The success of HSCT depends partly on finding a suitable donor. The best match is usually a sibling who shares the same tissue type, but matched unrelated donors or partially matched family members can also be used. Before transplant, patients receive a conditioning regimen to eliminate their existing immune cells and create space for the donor cells. After transplant, patients require intensive monitoring and supportive care as the new immune system establishes itself, a process that can take many months. Even after successful engraftment, patients face ongoing risks and require long-term follow-up.
The availability of new targeted therapies like leniolisib may reduce the number of people who need HSCT by providing better disease control with less risk. However, transplantation remains an important option for those with severe disease, and research continues to improve transplant techniques and reduce complications.
Beyond specific therapies targeting the immune deficiency, comprehensive APDS care includes addressing various symptoms and complications. Regular monitoring is essential and typically includes periodic pulmonary function tests to assess lung health, imaging studies to evaluate for bronchiectasis or lymphoproliferation, blood tests to check antibody levels and blood cell counts, and screening for autoimmune complications.
For gastrointestinal symptoms, which can include chronic diarrhea, abdominal pain, or inflammatory bowel disease resembling Crohn's colitis, treatment may involve dietary modifications, anti-inflammatory medications, or immunosuppressive therapies. Some individuals develop nodular lymphoid hyperplasia in the intestines, which are benign growths of lymphoid tissue that can sometimes cause complications like intussusception (where one part of the intestine slides into another). These situations may require surgical intervention.
Growth and development concerns are common in children with APDS, who may experience short stature, growth delays, or neurodevelopmental delays. These problems appear to be more prominent in APDS type 2, though they can occur in both types. Addressing these issues may involve growth hormone therapy, nutritional support, and developmental services including physical, occupational, or speech therapy depending on individual needs.
Because APDS increases the risk of developing lymphomas (blood cancers), particularly Hodgkin lymphoma and non-Hodgkin lymphoma, regular screening is important. Any persistent, enlarging, or hard lymph nodes should be evaluated promptly, potentially with biopsy if concerning. If lymphoma develops, treatment typically involves chemotherapy, sometimes combined with radiation therapy, following standard oncology protocols. The presence of an underlying immunodeficiency can complicate cancer treatment, requiring close coordination between oncologists and immunologists.
Dental care deserves special attention, particularly in people with APDS type 2, who may experience characteristic dental findings including abnormalities in tooth development or increased susceptibility to dental infections. Regular dental check-ups, good oral hygiene, and prompt treatment of dental problems are important aspects of overall health management.
This guide is here to help you understand the condition. It does not replace a conversation with your doctor, who knows your situation best.
Tell us about your condition – we search every trial in Europe and connect you with the right site.
