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E. Van Den Neste et al.
of PD-L1/L2 expression, which confers an immune privi- lege to HRS cells. Chromosome 9p24.1/PD-L1/PD-L2 alterations increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and their further induction through JAK/STAT signaling.26-28 This complex crosstalk between malignant HRS cells and the reactive microenvironment could be targeted to overcome chemoresistance. Based on this rationale, we explored JAK 1/2 inhibition in a phase II study of fixed dose ruxolitinib in patients with advanced HL patients before the onset of the era of PD-1 blockers. With an ORR of 9.4% at the end of the 6-month induction period, this study did not reach its primary effi- cacy goal. Nevertheless, when including transient responses seen before the 6-month evaluation, the ORR was 18.8% in some heavily pretreated patients, most of whom were refractory and had failed treatment with BV. These responses were sometimes durable (median=7.7 months). Some other patients had disease control, but with uncertain clinical benefit. A notable finding to be highlighted was the relief of B symptoms and pruritus, which was quick and long-lasting, resulting in a number of patients being reluctant to discontinue the compound, despite progressive disease. The latter effect should not be interpreted as a proven surrogate of anti-lymphoma activity.
These results tend to lend some support to the concept of JAK1/2 inhibition as a potential therapeutic means in HL. There are presently only scarce data available on the use of ruxolitinib in HL. In a preliminary report of an ongoing study, Kim et al. described rapid achievement of disease control (1 complete response, 5 partial responses, 1 stable disease) in 13 patients with advanced HL treated with ruxolitinib at a dose of 20 mg bid.29 Younes et al. reported changes in tumor measurements in HL patients treated in a phase I study with SB1518, an inhibitor of JAK2 and FLT-3.30 In vitro, AZD1480, an inhibitor of JAK1 and JAK2, could regulate proliferation in HL cell lines.27 The multikinase inhibitor lestaurtinib also inhibited growth and increased apoptosis of HL cell lines and HL cells from lymph nodes.31 Finally, a clinical grade JAK2 inhibitor, fedratinib, inhibited the proliferation of classi- cal HL cell lines in a JAK2 copy number-dependent man- ner implying decreased phosphorylation of STAT and expression of downstream targets including PD-L1 show- ing immunomodulation by JAK inhibitors.32
If JAK2 is actually an appropriate target, questions arise as to why the study outcome was not more convincing. Could the drug's limited activity be attributed to insuffi- cient dosage? Given that we observed unambiguous cytokine profile changes and frequent improvements in B symptoms, it would seem that the dosage of 20 mg twice daily, a dosage at which target inhibition occurs in myelofibrosis,33 was appropriate. Another factor possibly influencing the outcome was our patients’ disease stage, represented by a high percentage of refractoriness. At this late stage, the genetic changes would be so complex that selective inhibition of JAK is insufficient in cells depend- ent on other signaling pathways to promote their sur- vival, thus further curbing the study's potential. It is known that genomic aberrations, such as chromosome breakpoints, are more numerous in later clinical stages of HL.34 Mechanisms of resistance to JAK/STAT inhibition have been reported such as a feedback loop of paradoxi- cally activated extracellular signal-regulated kinases 1 and 2 (ERK1/2).27 Aberrations of the 9p24.1 amplicon, which
Table 4. Treatment-emergent adverse events. A. Patients with an adverse event. Treatment-emergent adverse events1
Patients with > 1 AE
N. of AE/patient, median (range) N. of patients with AE > grade 3
Patients with AE related to ruxolitinib
Patients with AE leading to drug discontinuation
Patients with AE leading to death
AE: adverse event. 1Total number of AE, 40.
All patients (n=33)
14 (42.4%) 2 (1-11) 8 (24.2%)
6 (18.2%) 1 (3%) 0 (0%)
B. Characteristics of the adverse event (N = 40) by system organ class and preferred terms
Adverse event
Any adverse event
Infections and infestations Anemia
Lymphopenia Thrombocytopenia
Weight decrease
Respiratory and thoracic disorders
Diarrhea
Infuenza-like illness
Subdural hematoma
Bonepain
Epilepsy
Any grade
40
13
11
4
2
1
3
1
1
1
1
2
Grade 2
15
10 0 0 0 0 2 1 1 0 1 0
contains the JAK2 gene, are more frequent
disease.28 Surprisingly, in our patients, a low
JAK2 amplification was seen, suggesting a low proportion of patients harboring the target of ruxolitinib, although this inference should be considered with caution since not all patients could be analyzed.
With respect to safety, ruxolitinib was by and large well-tolerated, with no drug-related mortality reported. The most prominent toxicities included drug-related ane- mia and manageable infectious events with no specific pattern. The relative lack of hematologic toxicity suggests that it could be feasible to combine ruxolitinib treatment with genotoxic compounds. For patients who discontin- ued ruxolitinib therapy, a switch to chemotherapy and/or immunotherapy was feasible, suggesting that the com- pound does not jeopardize further treatment.
The question now remains as to how this compound can best be utilized in the future. The exploratory nature of our study did not allow identification of the best can- didates on the basis of clinical stage or biomarkers. The cytokine profile showed some changes in patients with pruritus, but these changes were not correlated with clin- ical response. Although JAK2 status was explored in a minority of patients, the only patient with JAK2 amplifi- cation achieved a response. It will be important to focus on biomarker results in ongoing studies of JAK inhibition in HL. Given ruxolitinib’s limited benefits as monothera- py, use in combination with other drugs may possibly enhance its therapeutic potential. Ruxolitinib, which has no overlapping toxicity with chemotherapy, has been combined with hypomethylating agents, lenalidomide,
Grades > 3
25
31 11 4 2 1 1 0 0 1 0 2
846
1Implantable device infection, gastro-enteritis, lung infection.
haematologica | 2018; 103(5)
in advanced incidence of