A new reduced-intensity conditioning (RIC) regimen based on targeted busulfan prior to allogeneic hematopoietic stem cell transplant (HSCT) may be an effective and safer approach to treat hemophagocytic lymphohistiocytosis (HLH), a multi-center study shows.

However, long-term studies including patients with all known HLH-causative mutations are needed to confirm the benefits of this approach in this patient population, the researchers noted.

The study, “Targeted busulfan-based reduced-intensity conditioning and HLA-matched HSCT cure hemophagocytic lymphohistiocytosis,” was published in the journal Blood Advances.

HLH is characterized by excessive inflammation and organ damage due to overactivation of the immune system. Allogeneic HSCT remains the only effective cure to the primary form of HLH, which is caused by mutations in genes that control immune system activity and typically emerges during childhood.

Allogeneic HSCT is based on the transplant of healthy hematopoietic stem cells (HSC) — cells that can form all types of blood cells in the body — from a genetically identical donor (allogeneic) to replace the patient’s diseased cells.

Before a patient can receive the transplant, his/her own blood cells need to be depleted — through chemotherapy, for instance — for a subsequent successful reconstitution with donor cells.

Standard myeloablative conditioning regimens are intensive approaches that result in the complete destruction of bone marrow cells, including HSC. While these regimens increase the likelihood of a successful transplant, they are associated with higher toxicity, transplant-related complications, and mortality.

With the goal of reducing such negative effects, researchers developed regimens that use less chemotherapy and radiation than the standard myeloablative conditioning, known as RIC (reduced-intensity conditioning).

However, because RIC regimens may not achieve a complete destruction of the patients’ blood cells, there is a higher risk of transplant failure, incomplete reconstitution or donor chimerism, HLH relapses, and graft-versus-host disease (GVHD). (A complete donor chimerism means that all blood cells in the patient are of donor origin, and GVHD happens when the transplanted immune cells see the recipient’s body as foreign.)

A previous study showed that a RIC regimen based on targeted busulfan (a type of chemotherapy) resulted in excellent effectiveness and low toxicity in high-risk pediatric and adult patients with chronic granulomatous disease, a form of immunodeficiency.

Now, researchers evaluated the effects of this new RIC regimen in 25 people with primary HLH undergoing allogenic HSCT within a collaborative multi-center study led by the Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation (IEWP EBMT).

Genetic testing showed the presence of mutations in several HLH-associated genes in 23 patients, but failed to clearly identify causative mutations in two others. Central nervous system (brain and spinal cord) involvement was present in 25% of patients.

Participants were treated at a median age of 8.2 months (range 2 months to  22 years) at seven European pediatric stem cell therapy centers. A total of 18 patients received a HSCT from an unrelated genetically identical donor, while seven received it from a relative.

The RIC regimen consisted of busulfan (targeted to achieve a total exposure of 45–65 micrograms per liter per hour, fludarabine (an injected chemotherapy), and serotherapy to prevent GVHD. This busulfan-targeted regimen was expected to lower the rate of transplant failure and increase donor chimerism.

Researchers assessed patients’ overall survival, the rate of transplant success, GVHD, and donor chimerism in several blood cell subtypes, as well as the regimen’s toxicity.

Data at last follow-up (median of three years) showed that all patients were alive and had no signs of HLH relapses. All transplants were successful and resulted in sufficient, curative donor chimerism in several blood cell subtypes — with a median value higher than 97% — without the need for additional cell therapies.

Importantly, none of the patients developed acute severe GVHD and only one patient (4%) showed limited chronic GVHD.

While the regimen’s overall toxicity was low, eight patients (32%) developed sinusoidal obstruction syndrome (a liver condition associated with chemotherapy), which was resolved after treatment with defibrotide.

The team suggested that lowering total exposure to busulfan and treating infants with preventive defibrotide could lower the risk for sinusoidal obstruction syndrome in this patient population.

Overall, the findings suggested that a targeted busulfan-based regimen plus HSCT resulted in “high cure rates and successful prevention of [transplant failure] and GVHD in patients with various types of HLH,” the researchers wrote.

The team also emphasized that real-time monitoring of busulfan total exposure was essential, as a wide range of busulfan doses were found to achieve the target exposure. This means that without this real-time monitoring, full-dose busulfan might have led to toxic effects in some patients with slow therapy clearance and insufficient blood cell depletion in those with rapid therapy clearance.

More studies are needed to confirm these findings, they noted.