HLHRUXO: Ruxolitinib Therapy for HLH

Brief Summary

This is a multi-institution Phase Ib/II study to determine the efficacy and tolerability of a response-adapted regimen incorporating ruxolitinib (Jakafi®), dexamethasone and etoposide as frontline therapy for patients with newly diagnosed hemophagocytic lymphohistiocytosis or as salvage therapy for patients with relapsed/refractory HLH. The trial will be coordinated by the North American Consortium of Histiocytosis  (NACHO) with enrollment at St. Jude and eight (8) additional sites throughout the United States.

HLH is a rare and often fatal disorder of the immune system characterized by the overwhelming activation of T cells and macrophages, which secrete high levels of cytokines and mediate significant tissue damage. Current treatment primarily focuses on decreasing inflammation and treating any underlying triggers by using agents such as high-dose steroids, etoposide, ATG and alemtuzumab. Although these treatments have helped reduce mortality, they are associated with short- and long-term toxicities and five-year survival remains around 60%.

Recent research efforts have focused on developing new targeted therapies to suppress the cytokines that fuel HLH. Many of the cytokines that are elevated in the HLH signal occur via the JAK-STAT pathway. Ruxolitinib is a JAK1/2 inhibitor that has been shown in preclinical studies to decrease the manifestations of HLH, reduce CNS inflammation and significantly increase survival. This novel immunomodulatory agent offers a rational therapy that can be used instead of, or in some cases, in addition to, other HLH-directed therapies, such as etoposide.

Primary Objective

• To determine the efficacy and tolerability of a response-adapted ruxolitinib-containing regimen for patients with newly diagnosed HLH.

Secondary Objectives

• To describe the efficacy and tolerability of a response-adapted ruxolitinib-containing regimen for patients with relapsed/refractory HLH
• To describe the overall response and outcome for patients with newly diagnosed or relapsed/refractory HLH who are treated with this regimen

Eligibility Criteria

Inclusion criteria include:

•  ≥6 weeks to 22 years old
• Newly diagnosed HLH
• History of HLH unresponsive to prior therapy

Exclusion Criteria include but are not limited to:

• Weighs less than 3 kg
• Isolated CNS disease
• Life expectancy less than 2 weeks
• Likely to require less than 4 weeks of therapy
• Severe organ dysfunction
• Taking rifampin, St. John’s Wort or any JAK inhibitor
• Taking another investigational agent or enrolled on another treatment protocol

Study Design

Multi-site Phase Ib/II, two-arm (Frontline and Salvage), non-randomized clinical trial.

Study Sites

St. Jude Children’s Research Hospital
Memphis, Tennessee

Collaborating sites in the U.S.

About this study

This study will test a new drug therapy for hemophagocytic lymphohistiocytosis . This condition is also known as HLH or HLH disease.

The drug in this study is called ruxolitinib  (Jakafi). The U.S. Food and Drug Administration (FDA) has approved ruxolitinib to treat adults with certain blood disorders. The FDA has also approved the drug to treat a condition called steroid refractory graft-versus-host disease in adults and children at least 12 years old.

Research suggests ruxolitinib may reduce the immune system inflammation that happens with HLH. Studies also suggest ruxolitinib may work better than other HLH therapies.

Although studies have found that ruxolitinib is safe in children with cancer, we do not know the safest and best dose of this drug in children with HLH. This study will only use doses of ruxolitinib that have been shown to be safe when given to children with cancer.

Purpose of this clinical trial

This main goal of this study is to find out if ruxolitinib will improve the survival rate for children with HLH.

Eligibility overview

• 6 weeks to 22 years old
• Newly diagnosed HLH
• History of HLH unresponsive to prior therapy