Hodgkin lymphoma (HL) is a highly sensitive neoplasm to systemic combined chemotherapy. Despite the optimal response rate seen in HL patients, 10-15% exhibit a refractory/relapsed (R/R) disease course with a dismal prognosis. After treatment failure, high-dose chemotherapy and with autologous stem cell transplantation are warranted. Even in the presence of newly tailored agents, many R/R HL cases are regarded as palliative.1 Recent advances in transcriptome profiling have elucidated many altered pathways in HL, including immune evasion, NF-κB, PI3K/AKT/mTOR, and JAK/STAT. The latter is observed due to the classical 9p and 2p gains in HL.2 JAK is a cytoplasmic tyrosine kinase that modulates gene transcription by phosphorylating STAT factors. Although alterations in JAK/STAT pathway are commonly detected in myeloproliferative disorders and myeloid neoplasms, they play an important role in the tumorigenesis of HL. In the past decade, the therapeutic potential of JAK/STAT inhibition in HL has been conceptualized and popularized in many preclinical studies. Such rationale resulted in a group of clinical trials to evaluate the proposed hypothesis. Since ruxolitinib, an oral, selective inhibitor of JAK1/JAK2, was approved by the FDA in 2011 for myeloproliferative disorders, it was used in HL trials.
In 2014, Kim et al. published the first preliminary data of a multi-center, single-agent pilot study (NCT01965119) evaluating the 28-day cycle of 20 mg twice daily of ruxolitinib in patients with R/R HL. The study, in which 13 HL patients were enrolled, was finalized and published in 2019.3 The response rate was 54%, with one complete remission, one stable disease, and five partial remissions, with a median response duration of 5.6 months. Ruxolitinib showed an acceptable safety profile, with manageable grade 1 and 2 adverse events. Another multi-center, open-label, phase II clinical trial (NCT01877005) conducted at the Lymphoma Study Association (LYSA) centers evaluated ruxolitinib in 33 patients with advanced R/R HL.4 The response rate was poor in those who received more than 6 cycles, with only three patients exhibiting partial response and 11 with stable disease. The median response duration, 7.7 months, was longer than the previous study. The reported median progression-free and median overall survival were 3.5 and 27.1 months, respectively. Ruxolitinib showed limited toxicity and an acceptable safety profile, in which 42.4% of the participants had a side event, with only one that led to treatment discontinuation. The JeRiCHO trial (NCT02164500), a 2-stage phase 2 design, open-label, multi-center clinical trial, evaluated the effect of 25 mg twice daily ruxolitinib in R/R classical HL.5 The trial enrolled 12 patients in the first stage. Only one had a partial response, with the rest having stable (three patients) or progressive (six patients) disease course. Progression-free survival was 3.6 months, while the 1-year overall survival was 50.6%, with a favorable toxicity profile. The reported data suggest that ruxolitinib has a modest short-lived, and limited potential in HL patients, with a highly acceptable safety profile. Additional studies with expanded cohorts are warranted to conclude.
The observed effect could be augmented if ruxolitinib got incorporated with other agents. Hence, the synergetic potential of combining ruxolitinib with other medications in R/R HL is of great interest for clinical evaluation. In Phase I/II, multi-center, open-label trial (NCT03681561) evaluating the efficacy, safety, and tolerability of ruxolitinib combined with nivolumab for R/R HL after immune checkpoint inhibitor therapy failure,6 a total of 19 patients were enrolled, of which 16 were eligible for response evaluation. The best overall response rate was 75%. Three patients experienced complete remission, two a partial remission, and six patients remained in stable disease. The 1-year progression-free survival was 64%. The combination therapy showed proper safety and tolerability; the most adverse events were grade 1 and 2, with a minority requiring hospitalization or having immune-related events. The reported data are preliminary but show a promising potential for dual JAK2 and PD-1 blockage, with encouraging synergistic activity. In an ongoing trial evaluating ruxolitinib with etoposide and corticosteroids in heavily pretreated HL and non-HL patients, the preliminary report showed only 1 enrolled patient with HL exhibiting a stable disease course and progression-free survival of 102 days without adverse events.7 The combinations of ruxolitinib with pembrolizumab (NCT04016116) or bortezomib (NCT02613598) in HL are being investigated in two distinct ongoing clinical trials.
In conclusion, ruxolitinib monotherapy in R/R HL shows limited efficacy, safe profile, and little toxicity. Table 1 summarizes all the published data on the utilization of ruxolitinib in R/R HL. In contrast, combination therapy with immune check-point inhibitors or other chemotherapeutic agents could exhibit significant efficacy; it is too early to conclude such fact without comprehensive trials with large cohorts and detailed molecular studies.
Table 1. Summary of clinical trials evaluating the safety and efficacy of ruxolitinib or ruxolitinib-based regimen in R/R HL.
| Regimen type | Number of patients enrolled | Regimen dosages | Patients’ response | Median response duration (months) | Adverse events grading | NCT number | Reference |
| Ruxolitinib monotherapy | 13 | Ruxolitinib: 20 mg twice daily for a 28-day cycle. | 6 (one CR, five PR, and one SD) | 5.6 | G1-G2 | NCT01965119 | 3 |
| 33 | Ruxolitinib: 20 mg twice daily for a 28-day cycle. | 20 (six CR, three PR, and 11 SD*) | 7.7 | G1-G3 | NCT01877005 | 4 | |
| 12 | Ruxolitinib: 25 mg twice daily for a 28-day cycle. | 5 (Zero CR, two PR, and three SD) | 5.6 | G1-G4 | NCT02164500 | 5 | |
| Ruxolitinib-based combined regimens | 16 | Ruxolitinib: 10, 15, and 30 mg twice daily and nivolumab:3mg/kg IV every 2 weeks) for 2 years. | 12 (three CR, two PR, and six SD) | 12.5 | G1-G3 | NCT03681561 | 6 |
| 1 | Ruxolitinib: 10 or 5 mg twice daily for a 28-day cycle and etoposide: 50mg/m2 with prednisone: 0 or 5 mg/kg daily. | 1 (one SD) | - | No adverse events | Not registered. | 7 |
CR: complete response, PR: partial remission, and SD: stable disease.
*SD was transient.
Ethical Approval
Not applicable.
Consent to participate/Informed Consent
Not applicable.
Consent for publication
Not applicable.
Competing interests/ Conflict of Interest
Not applicable.
Authors’ Contribution – CRediT taxonomy
Conceptualization: Ahmed H. Al Sharie, Balqis M. Abu Mousa, Ahmad O. Alomari; Methodology: Ahmed H. Al Sharie, Balqis M. Abu Mousa, Ahmad O. Alomari; Formal analysis and investigation: N/A; Writing - original draft preparation: Ahmed H. Al Sharie, Balqis M. Abu Mousa, Ahmad O. Alomari; Writing - review and editing: Ahmed H. Al Sharie; Funding acquisition: N/A; Resources: N/A; Supervision: Ahmed H. Al Sharie.
References
- Latest advances in the management of classical Hodgkin lymphoma: the era of novel therapies. Mohty Razan, Dulery Rémy, Bazarbachi Abdul Hamid, Savani Malvi, Hamed Rama Al, Bazarbachi Ali, Mohty Mohamad. Jul 9;2021 Blood Cancer Journal. 11(7):126. doi: 10.1038/s41408-021-00518-z. doi: 10.1038/s41408-021-00518-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Genetic lesions and targeted therapy in Hodgkin lymphoma. Li Zhe, Mu Wei, Xiao Min. Jan;2023 Therapeutic Advances in Hematology. 14:2040620722114925. doi: 10.1177/20406207221149245. doi: 10.1177/20406207221149245. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ruxolitinib shows activity against Hodgkin lymphoma but not primary mediastinal large B-cell lymphoma. Kim Seok Jin, Yoon Dok Hyun, Kang Hye Jin, Hong Jung Yong, Lee Ho Sup, Oh Sung Yong, Shin Ho-Jin, Kong Jee Hyun, Yi Jun Ho, Sakamoto Kana, Ko Young Hyeh, Huh Jooryung, Lee Seung-Sook, Takeuchi Kengo, Shin Dong-Yeop, Suh Cheolwon, Kim Won Seog. Nov 10;2019 BMC Cancer. 19(1):1080. doi: 10.1186/s12885-019-6303-z. doi: 10.1186/s12885-019-6303-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- A phase II study of the oral JAK1/JAK2 inhibitor ruxolitinib in advanced relapsed/refractory Hodgkin lymphoma. Van Den Neste Eric, André Marc, Gastinne Thomas, Stamatoullas Aspasia, Haioun Corinne, Belhabri Amine, Reman Oumedaly, Casasnovas Olivier, Ghesquieres Hervé, Verhoef Gregor, Claessen Marie-José, Poirel Hélène A., Copin Marie-Christine, Dubois Romain, Vandenberghe Peter, Stoian Ioanna-Andrea, Cottereau Anne S., Bailly Sarah, Knoops Laurent, Morschhauser Franck. Jan 19;2018 Haematologica. 103(5):840–848. doi: 10.3324/haematol.2017.180554. doi: 10.3324/haematol.2017.180554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- JAK inhibition with ruxolitinib in relapsed or refractory classical Hodgkin lymphoma: Final results of a phase II, open label, multicentre clinical trial (JeRiCHO) Gillessen Sarah, Pluetschow Annette, Vucinic Vladan, Ostermann Helmut, Kobe Carsten, Bröckelmann Paul J., Böll Boris, Eichenauer Dennis A., Heger Jan-Michel, Borchmann Sven, Fuchs Michael, Borchmann Peter, Engert Andreas, von Tresckow Bastian. Oct 3;2022 European Journal of Haematology. 109(6):728–735. doi: 10.1111/ejh.13859. doi: 10.1111/ejh.13859. [DOI] [PubMed] [Google Scholar]
- Ruxolitinib Plus Nivolumab in Patients with R/R Hodgkin Lymphoma after Failure of Check-Point Inhibitors: Preliminary Report on Safety and Efficacy. Bachanova Veronika, Hegerova Livia, Cao Qing, Janakiram Murali, Maakaron Joseph, Ayyappan Sabarish, Weisdorf Daniel J., Zak Jaroslav, Farooq Umar, Kenkre Vaishalee P. Nov 5;2021 Blood. 138(Supplement 1):230. doi: 10.1182/blood-2021-149675. doi: 10.1182/blood-2021-149675. [DOI] [Google Scholar]
- Ruxolitinib in Combination with Orally Etoposide and Corticosteroids (REC) Is Safe and Effective in Heavily Pretreated Hodgkin and Non-Hodgkin Lymphomas. Parcelier Anne, Morel Pierre, Royer Bruno, Delette Caroline, Leduc Isabelle, Sevestre Henri, Marolleau Jean-Pierre. Dec 3;2015 Blood. 126(23):3962. doi: 10.1182/blood.v126.23.3962.3962. doi: 10.1182/blood.v126.23.3962.3962. [DOI] [Google Scholar]