Daratumumab effective as CAD treatment in over half of patients

Medicine is an anticancer therapy approved for multiple myeloma

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Daratumumab, given on its own, could be a treatment for adults with hard to treat cold agglutinin disease (CAD), with more than half of the patients in a small study in Europe responding well to the therapy.

The findings add to previous reports about the successful use of daratumumab, an anticancer medication sold as Darzalex, to treat CAD patients when the disease is refractory, or resistant to previous treatments.

The study, “Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease,” was published in Blood Advances.

CAD is a type of autoimmune hemolytic anemia (AIHA), a group of rare autoimmune conditions wherein self-reactive antibodies are produced that wrongly attack red blood cells. This marks the cells for destruction, resulting in too few red blood cells (anemia) and poor oxygen transport throughout the body. In CAD, these antibodies bind to red blood cells at low temperatures. In warm AIHA, the most common type of AIHA, they are active at warm temperatures.

The first-line treatment for AIHA is usually steroids, which weaken the immune response. If patients don’t respond to steroids, doctors may prescribe rituximab, which targets a protein called CD20 on B-cells, the immune cells responsible for producing antibodies, causing them to die.

But off-label treatment with rituximab — sold as Rituxan in the U.S. and MabThera in Europe, with generics available — may also fail, perhaps due to “expansion of auto-reactive long-lived plasma cells lacking CD20,” the researchers wrote. Plasma cells are the most mature form of B-cells that produce large amounts of antibodies.

Evidence suggests daratumumab may be effective for people with hard to treat AIHA. Approved for multiple myeloma, a cancer where plasma cells grow out of control, the therapy targets CD38, a protein found at high levels on the surface of B-cell precursors and plasma cells.

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Proof-of-concept study data on CAD treatment expected later this year

Effects of daratumumab on CAD, AIHA

Here, researchers in five European countries retrospectively reviewed the medical files of 19 adults (median age, 56) with AIHA who were treated with daratumumab alone after they failed to respond to a median of five other medications. Twelve patients had warm AIHA and seven had CAD, two of whom have been reported in the literature.

Daratumumab was administered as an infusuon into the vein and/or under the skin. Three CAD patients received a fixed regimen of eight weekly doses while four were on monthly maintenance treatment.

The AIHA patients were followed for a median of five months and up to about three years, or 40 months. Two, one of each type of AIHA, died three months after daratumumab was started from severe hemolytic anemia, which occurs when red blood cells are destroyed faster than they can be replaced.

The patients in the CAD group had an initial median hemoglobin level of 8.6 g/dL, which is below normal. Hemoglobin is the protein in red blood cells that carries oxygen throughout the body. Low hemoglobin is a sign of anemia.

The patients received daratumumab for a median of 11 months. Four (57%) achieved a partial or complete response after a median of three weeks. A partial response was defined as a hemoglobin level of 10-12 g/dL or an increase by more than 2 g/dL, and a complete response was a level of more than 12 g/dL, in the absence of recent blood transfusions. Three patients achieved a complete response and the other showed a long-lasting partial response.

At the last follow-up, two of the three patients on monthly maintenance treatment continued to respond well after nearly a year. One patient’s disease progressed after about 1.5 years.

Two of the four patients who were dependent on blood transfusions before daratumumab became independent after three or six months.

Before daratumumab, all but one CAD patient had acrocyanosis, a bluish discoloration of the skin caused by a lack of oxygen-rich blood. After treatment, four (67%) reported clinical reductions, as early as two weeks, and two (33.3%) saw complete resolution after three and 12 months, respectively.

A similar response rate was reported in the AIHA patients, with six (50%) achieving a partial or complete response.

“Daratumumab monotherapy [alone] may be an effective and well tolerated treatment option associated with rapid responses for a proportion of refractory AIHA patients, with an effect on both the hemolytic anemia as well as the cold-induced circulatory symptoms,” the researchers wrote.

Blood sample analyses from two warm AIHA patients after daratumumab treatment showed depletion of both CD38-positive B-cells and CD38-positive T-cells, another type of immune cell. The reappearance of CD38-positive T-cells coincided with disease relapse in one patient.

“The observed immunomodulatory effects that may contribute to the clinical response deserve further exploration,” wrote the researchers, who said more studies are needed to confirm the effectiveness of anti-CD38 therapy in CAD and other AIHA types, and to see if maintenance therapy would help patients who respond initially.