Understanding warm autoimmune hemolytic anemia

Imagine your own immune system turning against you: not attacking a virus or a bacterium but destroying the very red blood cells your body needs to carry oxygen. That is the reality for people living with warm autoimmune hemolytic anemia, or warm AIHA.

Warm AIHA is a rare blood disorder in which the immune system produces antibodies — known as warm agglutinins, that mistakenly target and destroy a person's own red blood cells. These antibodies, almost always of the IgG type, bind to red blood cells at normal body temperature (37°C/98.6°F) and mark them for destruction, primarily in the spleen. The result is anemia: a shortage of red blood cells that leaves patients exhausted, short of breath and sometimes dangerously ill.

The condition affects roughly 1 to 3 people per 100,000 each year. It can strike at any age, though the median age of onset is around 52, and it is slightly more common in women. In about half of cases, no underlying cause is found. In the other half, it is linked to autoimmune diseases like lupus, blood cancers like chronic lymphocytic leukemia or immune deficiency disorders.

When autoimmunity hides in the shadows

For many patients with warm AIHA, the blood disorder is just the tip of the iceberg. Beneath the surface, an underlying autoimmune disease may be quietly driving the immune system's attack on its own red blood cells. Sometimes that disease is well-defined: systemic lupus erythematosus, Sjögren's syndrome or rheumatoid arthritis. But for others, the autoimmune process defies easy classification. Doctors may detect telltale autoantibodies in the blood and see signs of immune dysregulation, yet the full picture doesn't fit neatly into any single diagnosis. This is known as undifferentiated connective tissue disease, a condition in which the body is clearly at war with itself, but the enemy hasn't fully revealed its identity.

This diagnostic uncertainty adds another layer of burden for patients. They are fighting a disease they can see: the anemia, the fatigue, the jaundice — while living with the knowledge that something deeper and still undefined is fueling the fire.

Cathy's story: A life overshadowed by transfusions

Cathy was 55 years old when warm AIHA took over her life. A woman who had always prided herself on her independence and energy, Cathy found herself increasingly unable to do the things she loved. Her hemoglobin levels would plummet dangerously low, leaving her so fatigued she could barely walk across a room. Every few weeks, she found herself back in the hospital or clinic for another blood transfusion — a lifeline, but not a cure.

Cathy's treating physician, Dr. Kannan, MD, suspected that an underlying autoimmune disease was driving her warm AIHA, but the picture was frustratingly incomplete. Blood tests showed autoantibodies — markers of an immune system in overdrive — but her symptoms and lab results didn't fit squarely into lupus, Sjögren's or any other well-defined autoimmune condition. She was diagnosed with an undefined autoimmune disease, a label that offered little comfort and no clear road map for treatment.

Over the years, Cathy had tried nearly every available treatment for her warm AIHA. Corticosteroids helped at first but could not be sustained without serious side effects — weight gain, bone thinning, mood swings and a heightened risk of infection. Rituximab, a monoclonal antibody that targets B cells (the immune cells that produce antibodies), brought temporary relief, but the hemolysis always returned. Mycophenolate, azathioprine, intravenous immunoglobulin — one after another, each therapy was tried and found wanting. Cathy's direct antiglobulin test (the Coombs test, which detects the destructive antibodies coating her red blood cells) remained stubbornly positive. She was, in medical terms, "multi-refractory."

The cycle of transfusion dependence was relentless. Cathy's calendar revolved around hospital and clinic visits. She had to plan her life around infusion schedules, blood draws and the ever-present anxiety of wondering when her next crisis would come. Travel became impossible. Work became unreliable. The simple pleasures of daily life: a walk in the park, dinner with friends and travel for leisure were overshadowed by crushing fatigue and the fear that her hemoglobin could drop at any moment.

The hidden culprit: Long-lived plasma cells

The problem, Dr. Kannan explained, was that the treatments she had received targeted B cells. But in Cathy's case, the culprits were long-lived plasma cells: mature, antibody-secreting cells that had already graduated from the B-cell stage and settled deep in the bone marrow. These long-lived plasma cells do not carry the CD20 marker that rituximab targets. They were invisible to the drugs being used against them and they kept churning out the destructive antibodies that were destroying Cathy's red blood cells.

In patients with an underlying autoimmune disease, these rogue plasma cells can be especially persistent. The same immune dysregulation that drives the broader autoimmune process can help sustain these antibody-producing cells, creating a vicious cycle that standard therapies struggle to break.

A cancer drug finds a new purpose

Daratumumab (brand name Darzalex) was originally developed and approved for the treatment of multiple myeloma, a cancer of plasma cells. It works by targeting CD38, a protein highly expressed on the surface of plasma cells. By binding to CD38, daratumumab triggers the immune system to destroy these cells through multiple mechanisms including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and direct cell death.

Dr. Kannan hypothesized that if daratumumab could eliminate cancerous plasma cells in myeloma, it might also be able to wipe out the rogue, autoantibody-producing plasma cells driving Cathy’s hemolytic anemia. It was an off-label use, not yet approved for AIHA, but for a patient who had exhausted all standard options, the treatment represented a rational and evidence-based hope.

Cathy received daratumumab by intravenous infusion at the standard dose of 16 mg per kilogram followed by subcutaneous injections. The treatment was given with standard pre-medications to prevent allergic reactions, and she tolerated them without significant side effects.

The turning point

The response was remarkable. Within weeks of starting daratumumab, her hemoglobin, which had been hovering at dangerously low levels requiring regular transfusions, began to climb steadily.

Most importantly, Cathy stopped needing blood transfusions. For a woman whose life had revolved around hospital visits and the anxiety of wondering when her next crisis would come, this was transformative. Her energy returned. She began to reclaim the life that warm AIHA and her underlying autoimmune disease had stolen from her.

Cathy's hemoglobin stabilized at healthy levels and remained there through months of follow-up. Her markers of hemolysis, the laboratory signs that her red blood cells were being destroyed, normalized. For the first time in years, she was free from transfusion dependence.

Why daratumumab works where other treatments fail

The key to daratumumab's success in cases like Cathy's lies in its unique target. Standard therapies for warm AIHA: steroids, rituximab, splenectomy, primarily address B cells or the splenic destruction of red blood cells. But they leave long-lived plasma cells untouched. These plasma cells, which reside in the bone marrow and can survive for years, continue to secrete pathogenic autoantibodies even after B cells have been depleted.

Daratumumab directly targets these long-lived plasma cells through CD38. Research has shown that beyond simple plasma cell depletion, daratumumab also has broader immunomodulatory effects, influencing the dynamics of several immune-regulating cytokines. This dual action, eliminating the source of destructive antibodies while recalibrating the immune environment, may explain the depth and durability of responses seen in refractory cases.

For patients like Cathy, whose warm AIHA is driven by an underlying autoimmune disease, this approach is especially compelling. By going after the plasma cells that sit at the root of autoantibody production, daratumumab addresses the fundamental problem rather than just managing its downstream effects.

A growing body of evidence

While daratumumab is not yet approved for warm AIHA, a growing number of case reports and small series from centers around the world have documented its effectiveness in patients who have failed multiple prior therapies. Published reports describe patients achieving transfusion independence, normalization of hemoglobin and sustained remission after daratumumab treatment. The drug has shown efficacy in both adult and pediatric patients with refractory autoimmune hemolytic anemia, including cases occurring in the setting of systemic autoimmune diseases and after stem cell transplantation.

Clinical trials are now underway to formally evaluate daratumumab and related anti-CD38 therapies in warm AIHA, alongside other promising new therapies targeting different parts of the immune cascade, including Bruton tyrosine kinase inhibitors, spleen tyrosine kinase inhibitors, complement inhibitors and neonatal Fc receptor blockers.

What this means for patients

For the thousands of people living with warm AIHA, Cathy’s story offers hope — and reflects a broader shift toward precision therapies that target the specific cells and pathways driving disease.

Warm AIHA remains a serious and sometimes life-threatening condition. But the landscape is changing. As new therapies move from case reports to clinical trials and, potentially, approval, the goal is the same: stable hemoglobin, freedom from transfusions and the chance to live a full life.

Cathy’s story is a testament to the power of new approaches — and to the resilience of patients who refuse to give up hope, even when their own bodies seem to have turned against them.

Note: Cathy's story is shared with her involvement and is representative of real patient experiences documented in the medical literature. Daratumumab is not currently approved for the treatment of warm AIHA and is used off-label in this setting. Patients should discuss all treatment options with their healthcare team.