Combined Low-Dose Ruxolitinib and Emapalumab Treatment Demonstrates Efficacy for Patients With Hemophagocytic Lymphohistiocytosis

The combination of low-dose ruxolitinib and anti-interferon-gamma (IFN-gamma) antibody emapalumab demonstrated efficacy and safety for treating patients with hemophagocytic lymphohistiocytosis (HLH), according to a small retrospective analysis.

Emapulumab, has received FDA approval for treating refractory or recurrent pHLH or those intolerant to conventional HLH therapies. However, the necessity demonstrated for the addition of other therapies like dexamethasone implies that inhibiting IFN-gamma alone may not be sufficient for treating all patients.

“Ruxolitinib, a JAK 1/2 inhibitor, has proven effective in HLH by dampening downstream signaling of numerous cytokines,” explained Yue Song, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China, “However, previous clinical studies of ruxolitinib in HLH showed only partial effects. It is evident that neither IFN-gamma blockade nor ruxolitinib monotherapy can lead to complete disease control in HLH.”

Song and colleagues conducted a retrospective clinical analysis of 13 patients diagnosed with HLH who received a combination treatment of emapalumab and ruxolitinib. Patients received emapalumab at a dose of 50 to 100 mg (~1 to 2 mg/kg), and ruxolitinib of 20 to 30 mg/m²/day orally. In certain cases, study authors noted, corticosteroid, intravenous immunoglobulin (IVIG), and/or continuous renal replacement therapy were administered along with therapy. Additional chemotherapy was allowed following emapalumab and ruxolitinib if the physicians deemed the response inadequate.

Therapeutic response was assessed in accordance with established criteria, and had to be sustained for at least 3 days to be considered in the analysis. Study authors also assessed the adverse events related to therapy, the number of patients proceeding to HSCT, 2-month survival, overall survival, and cause of death. All of the patients included in this assessment were adults at 18 years or older, at a median age of 34 years old. There were 8 patients who received previous conventional therapy for HLH. Study authors observed that 5 out of 8 patients had not responded to previous treatment, while the other 3 experienced transient ameliorations followed by rapid relapses.

The median time of the patients’ clinical course, from the estimated onset of HLH symptoms to the first emapalumab infusion, was 4.6 weeks. In this course, 5 patients received 2 doses of emapalumab and 1 patient received 4 doses, while 3 patients received concomitant low-dose etoposide (50 mg/m²). The median duration of treatment received for emapalumab and ruxolitinib together was 1.14 weeks (interquartile range [IQR ]1.0 to 2.8 weeks) (6.7 weeks (IQR 3.6 to 9.4 weeks) for ruxolitinib and 1.14 weeks (IQR 1.0 to 2.8 weeks) for emapalumab, separately).

Overall, 77% of patients responded positively to therapy. Among them, 62% achieved remission, with 4 patients reaching complete response [CR] (31%) and another 4 achieving partial response [PR] (31%), while 2 patients showed improvement (15%) but did not meet the criteria for remission. In the remaining 3 patients, 2 experienced resolutions of fever but did not meet the criteria for improvement. 75% of previously treated relapsed/refractory patients and 80% of treatment-naive patients demonstrated a positive response.

All laboratory parameters of HLH quickly improved upon the initiation of emapalumab, with evident improvement at week 1 in the majority of patients. Among the 5 Epstein–Barr virus (EBV)-HLH patients, 4 also received PD-1 blockade during/after emapalumab, and the intracellular EBV-DNA copies significantly decreased in only 1 patient. Before treatment, interleukin-6 (IL-6) concentrations were significantly elevated in all patients, and IL-10 concentrations were elevated in 92%. However, IFN-gamma concentrations were variable across patients. Emapalumab administration resulted in a rapid decrease to normal levels of IFN-gamma in all patients. However, the decline in IFN-gamma was not associated with disease response. Instead, the decrease in IL-6 and IL-10 correlated with the therapeutic effect: decreased IL-6 levels were associated with response (p = 0.008) and remission (p = 0.025), and decreased IL-10 levels were associated with remission (p = 0.007) but not response (p = 0.066).

The median follow-up time was 5.8 months, and 5 patients (38%) proceeded to allo-HSCT, 4 patients died, and 4 patients survived. For cause of mortality, 3 patients died of HLH, and the other one suffered sudden cardiac death, which was unrelated to HLH. The estimated probability of survival from initiation of emapalumab was 72.9% at 2 months. Study authors noted that 3 of the 5 patients who underwent allo-HSCT survived until last follow-up, the other two died of HSCT-related complications such as infection. The estimated probability of overall survival at 5 months was 44.4%.

No grade 3 or higher drug-related adverse events were observed in any of the patients. Only 1 patient experienced persistent CMV infection, considered possibly related to emapalumab. The infection resolved after 3 weeks of standard antiviral treatment.

In this study, the low-dosage agents’ combination proved to have a beneficial effect. The dosage amounts may be a crucial factor. Study authors noted that given that IFN-gamma plays important immunoregulatory roles, complete blockade will exacerbate immune responses and could be detrimental to outcomes, whereas a relatively low dose may be beneficial. Additionally, they posited that a low dose of ruxolitinib could avoid adverse effects such as myelosuppression.

In conclusion, “the combination of low-dose ruxolitinib and anti-IFN-gamma antibodies is a more effective and safe treatment for HLH. This approach shows promise even in cases of EBV- and lymphoma-associated [secondary] HLH, which typically suffer a poor prognosis, as well as in relapsed/refractory HLH, offering the possibility of bridging to HSCT,” Song and colleagues concluded.

“The doses and schedules of these agents must be carefully titrated to confer maximum benefit,” they added.

Source:

Song Y, Zhou F, Du F, et al. Combined emapalumab and ruxolitinib in patients with haemophagocytic lymphohistiocytosis. Blood CancerJ. Published online April 24, 2024, doi: 10.1038/s41408-024-01056-0