mAb could provide targeted approach to HLH treatment
ASH Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—A monoclonal antibody (mAb) targeting interferon-gamma (IFNγ) has shown promise for treating hemophagocytic lymphohistiocytosis (HLH), according to a late-breaking abstract presented at the 2015 ASH Annual Meeting.
Results of an ongoing phase 2 study suggest the mAb, NI-0501, may be a feasible treatment option for patients with HLH who have demonstrated an unsatisfactory response to, or cannot tolerate, conventional therapy.
Nine of 13 evaluable patients achieved a “satisfactory response” to NI-0501, and no safety concerns were identified, said Michael Jordan, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
Dr Jordan presented these results at ASH as LBA-3.* The trial was sponsored by Novimmune.
“Treatment of HLH remains very challenging,” Dr Jordan noted. “Initial therapy is directed at trying to suppress the out-of-control immune response. In children that are at risk for recurrent episodes of HLH, they proceed to hematopoietic cell transplantation and, hopefully, this allows long-term survival.”
“First-line therapy has been defined in international trials and involves etoposide and dexamethasone. This regimen, as you might imagine, in children that present already with cytopenias, is myelosuppressive. It’s also broadly immune-suppressive. And although this does allow long-term survival in these children, there’s plenty of room for improvement in results.”
“[T]here is no standard of care for second-line therapy. Though there are no prospective data, children are increasingly treated with T-cell-depleting agents such as alemtuzumab and ATG, but this produces profound and long-lasting immune suppression. Though survival is not well-defined in these patients, it’s thought to be poor.”
In hopes of finding a new treatment option for HLH, Dr Jordan and his colleagues attempted to determine what drives the disease process. In preclinical studies, they identified IFNγ as a rational target in HLH. Blockade of IFNγ led to improved survival in mouse models.
The researchers also found elevated levels of IFNγ in patients with HLH. These preclinical and clinical data led to the development of NI-0501, a fully human, high affinity, anti-IFNγ mAb that binds to and neutralizes IFNγ.
Patients and treatment
In their phase 2 trial, Dr Jordan and his colleagues assessed NI-0501 in 16 patients—8 males and 8 females. Their median age was 1.2 years (range, 0.2-13). Twelve patients had causative mutations—FHL2 (n=4), FHL3 (n=2), FHL4 (n=1), GS-2 (n=3), XLP-1 (n=1), and XLP-2 (n=1). And 4 patients had central nervous system (CNS) involvement.
Two patients were receiving NI-0501 as first-line treatment, and the rest were receiving the mAb as second-line treatment. Patients had previously received dexamethasone (n=13), methylprednisone (n=2), etoposide (n=13), ATG (n=4), cyclosporine A (n=6), and “other” therapy (n=4).
NI-0501 was given at a starting dose of 1 mg/kg every 3 days, with possible dose increases guided by pharmacokinetic data and/or clinical response in each patient. The mAb was administered with dexamethasone at a dose of 5mg/m2 to 10 mg/m2, but dexamethasone could be tapered during the treatment course.
The treatment duration ranged from 4 weeks to 8 weeks, and the follow-up period was 4 weeks.
Response and survival
One patient was excluded from the analysis due to a lymphoma diagnosis after enrollment. Two patients are still receiving treatment, and 13 have completed treatment.
Among the patients who completed therapy, 4 had an insufficient response. Two of these patients died, and 2 proceeded to allogeneic hematopoietic stem cell transplant (HSCT) after receiving additional agents to control their disease.
Nine patients achieved a favorable response to NI-0501. Seven of these patients proceeded to HSCT, and 2 are awaiting HSCT with their disease well-controlled.
