Weathering the HLH storm and redesigning clinical trials Free

In this issue of Blood, Zhou et al present results of a prospective phase 2 trial demonstrating that early administration of ruxolitinib plus dexamethasone (Ru-D) is a feasible and effective induction strategy for adult hemophagocytic lymphohistiocytosis (HLH), with favorable outcomes, especially in non–malignancy-associated disease.¹ 

HLH is a rapidly progressive and often fatal syndrome of immune dysregulation characterized by excessive cytokine release, cytopenias, organ failure, and a high mortality rate. Adult HLH presents a distinct challenge: patients often present with no obvious trigger, ongoing organ dysfunction, and a narrow window for intervention. Although the HLH-94 and HLH-2004 protocols,² which have a significant chemotherapy component, have guided pediatric treatment for decades, these regimens are poorly tolerated in adults for whom new treatments are urgently needed.³ 

Zhou et al report results from a single-arm, phase 2 study testing a novel frontline combination---ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, and dexamethasone---in 28 adults with newly diagnosed HLH. The rationale is grounded in the biology of HLH in which elevated levels of cytokines, particularly interferon-γ, interleukin-6 (IL-6), and IL-10, are responsible for many of the clinical features of the syndrome. Ruxolitinib, already approved for other cytokine-driven diseases such as myelofibrosis and steroid-refractory graft-versus-host disease, inhibits signaling pathways central to HLH pathogenesis.⁴ Preclinical studies and small pilot trials suggested that ruxolitinib synergizes with corticosteroids not only by suppressing inflammatory cascades, but also by potentially restoring sensitivity of CD8⁺ T-cell subsets---which play a central role in HLH---to apoptosis.^5-7 

Zhou et al included patients without known triggers at the time of diagnosis. Although patients with a known lymphoma-associated HLH (LAHS) at enrollment were excluded from the study. However, 16 patients were ultimately diagnosed with LAHS during follow-up, based on biopsy results, which were not available at baseline. The remainder had non-LAHS. Patients received 8 weeks of Ru-D, with early transition to salvage or disease-specific therapy allowed for nonresponders. The 2-month overall survival rate, the primary end point, was 85.7%, which exceeded historical benchmarks. The 2-year overall survival was 75% in the non-LAHS group and 37.5% in the LAHS group, highlighting the impact of underlying malignancy on prognosis.

Importantly, the regimen was well tolerated. Despite baseline cytopenias, including thrombocytopenia at <50 × 10⁹/L in most of the patients, no dose reductions or discontinuations were needed. Most adverse events were grade I or II, and no unexpected toxicities were observed. Inflammatory markers, including ferritin, soluble CD25, and cytokines, declined rapidly within the first week, mirroring clinical improvement. These findings reinforce the value of JAK inhibition as a targeted anti-inflammatory strategy in HLH.

The study brings into relief important challenges in adult HLH clinical trial design. At diagnosis, the trigger is often unknown, and malignancies may not become apparent until days or weeks later. Prompt immunosuppression with Ru-D achieved good responses in the majority of patients and thus has the potential to serve as a bridge to definitive therapy, including chemotherapy or hematopoietic cell transplantation.

The study also raises a broader question regarding response assessment in adult HLH. Although 24 (85.7%) patients met the response criteria, only 5 (17.9%), mostly patients who were non-LAHS, achieved complete response, and some patients who did not meet strict response criteria still showed clinical improvement. The authors have proposed a more flexible concept of “near complete response,” which may be appropriate in adult HLH, where laboratory normalization may lag behind meaningful clinical recovery. However, they stopped short of defining this category, leaving it as an open question for future studies.

The work supports the growing use of ruxolitinib early in the treatment of adult HLH. It works quickly, has manageable toxicity, and modulates key cytokine pathways, making it an attractive alternative to etoposide-based regimens, particularly in patients without a diagnosis of malignancy.

However, before widespread adoption of the Ru-D regimen can be recommended, it requires validation by way of a randomized clinical trial, which is a complex and ambitious undertaking in adult HLH. Although the authors suggest comparing the Ru-D regimen with HLH-94–based protocols, such an approach may not be ideal because of an intrinsic imbalance in the toxicity profile of the protocols and their markedly different mechanisms of action. In current clinical practice, adult HLH management increasingly follows a trigger-directed strategy for early control of hyperinflammation, and many experts favor less toxic immunomodulatory therapies such as anakinra, a recombinant human IL-1 receptor antagonist,⁸ to control hyperinflammation. A large retrospective study showed that anakinra was associated with superior outcomes when compared with etoposide.⁹ We propose that future trials directly compare ruxolitinib and anakinra (which was not used by Zhou et al) in adult HLH and include patients with hematologic malignancies, the commonest and most clinically significant trigger of secondary HLH.¹⁰ 

In conclusion, Zhou and colleagues provide compelling evidence that Ru-D is a safe and effective initial regimen for adult HLH, particularly when the underlying trigger remains unclear. Their findings advance the field toward a more tailored, biology-informed approach to treating this complex and heterogeneous syndrome.

Conflict-of-interest disclosure: A.Z.-L. serves on the advisory board and received consulting fees from Sobi. M.E. declares no competing financial interests.