Page 109 - Haematologica-5

Introduction
Methods
Hodgkin lymphoma (HL) is regarded as a curable malig- nancy in most cases, yet treatment failure still occurs in about 10% of patients with early-stage disease.1 In advanced-stage disease, up to 10% of cases do not reach complete remission and are thus considered to have pri- mary refractory HL,2 while 20-30% of primary responders eventually relapse following first-line treatment.3
For most patients with relapsed or refractory HL (R/R HL), the standard of care consists of high-dose salvage chemotherapy followed by autologous stem-cell transplan- tation (SCT). For patients who develop R/R HL within 1 year of autologous SCT, the prognosis proves extremely poor, since they have a median survival of 1.2 years.4 For patients in whom all classical approaches have failed, new strategies, including checkpoint inhibitors targeting PD-1 and antibody-drug conjugates targeting CD30, have become part of the therapeutic armamentarium against R/R HL.5-8 However, patients with multiple relapses or those who develop refractory disease remain in medical need, especially those in whom treatment with brentux- imab-vedotin (BV) and PD-1 blockers fails.
Classical HL is characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells and their vari- ants.9 HRS cells were demonstrated to shape their envi- ronment by secreting immunosuppressive cytokines and chemokines.10 With this in mind, the Janus kinase (JAK) – signal transducer and activator of transcription (STAT) pathway appears to be a relevant cytokine-induced signal transduction pathway that has been shown to transfer sig- nals directly from cell surface cytokine receptors to the cell nucleus. Given that enhanced JAK-mediated signaling has been demonstrated in a significant number of HL patients,11 this signaling pathway has become a focus for developing novel therapeutic agents for the disease. Van Roosbroeck et al. reported the translocation of JAK2 in several cases of HL,12 and JAK inhibition was shown to decrease the proliferation of cell lines. Although such translocations are relatively rare, 9p24.1 genomic amplifi- cation including the JAK2 locus appears common in HL, along with increased protein expression and activity, resulting in the constitutive activation of STAT6, an essen- tial messenger of tumor cell growth.13-15 In corollary, JAK 1/2 inhibition may be suitable to target the constitutive activation caused by either JAK2 translocation or JAK2 amplification and to modify the reactive microenviron- ment which contributes to HL growth via aberrant cytokine production.16
Ruxolitinib is the first potent, selective, and oral inhibitor of JAK1/2 being developed for clinical use.17 Its major effects include inhibition of proliferation, induction of apoptosis, and reduction in cytokine plasma levels, all mediated by the drug's ability to inhibit JAK-induced phos- phorylation of STAT.18 Used in the treatment of myelofi- brosis, ruxolitinib had durable efficacy in reducing splenomegaly and alleviating constitutional symptoms, the patients gained weight and their general physical condition improved.19 The dose-limiting toxicity was thrombocy- topenia, which was fairly well managed by dose reduc- tions or brief interruptions of treatment. In the present phase II study, we sought to investigate the safety and effi- cacy of ruxolitinib in patients with R/R HL. Exploratory biomarker analyses pertaining to plasma cytokine profiles and aberrations of JAK2 were also carried out.
Patients’ eligibility
Patients aged 18 years or older with a diagnosis of R/R HL for whom no treatment with proven efficacy was available were eli- gible to enter the trial after having receiving at least one prior therapy provided that they had measurable nodal disease at baseline (≥1 cm in the longest transverse diameter, clearly meas- urable in at least two perpendicular dimensions) on computed tomography or magnetic resonance imaging, as well as an Eastern Cooperative Oncology Group performance score of ≤3. Additional inclusion criteria were an absolute neutrophil count ≥1.0 x 109/L, platelet count ≥75 x 109/L, serum creatinine ≤1.5 x upper limit of normal, serum bilirubin ≤1.5 x upper limit of nor- mal, and ALT and AST levels ≤2.5 or ≤5.0 x upper limit of nor- mal in the event the transaminase increase was due to HL-relat- ed liver disease. Pregnant or lactating patients were not allowed to enter the trial, and men and women of childbearing potential had to agree to employ an adequate contraceptive method dur- ing the study treatment. Patients were permitted to have received an undefined number of prior lines of therapy, and a previous allogeneic SCT was likewise allowed provided that patients had not received any immunosuppressive therapy with- in the 90 days prior to starting the screening procedures. Patients were required to have a life expectancy of ≥3 months.
Study design and treatment
This multicenter, open-label, phase II study (HIJAK, NCT01877005) was conducted at ten LYSA centers in France and Belgium, with patients recruited from July 2013 through December 2014. Its primary efficacy endpoint was overall response rate (ORR), defined as the proportion of patients with a complete response or partial response at 6 months of treatment by investigator assessment based on the revised 2007 International Harmonization Project response criteria for malignant lym- phoma.20 Secondary objectives included relief of B symptoms, best ORR (occurring at any time during study), duration of response, progression-free survival, overall survival, as well as the incidence and severity of adverse events.
The study was carried out in line with the ethical principles of the Helsinki Declaration and in compliance with the International Conference on Harmonization Guideline for Good Clinical Practice. The protocol was approved by the institutional review board of each study site and written informed consent was obtained from all patients.
The starting dose of ruxolitinib was 20 mg given twice daily dur- ing six 28-day cycles for the induction period if the platelet count was >200 x 109/L. The ruxolitinib dose was decreased to 15 mg twice daily in patients with platelet counts between 75 x 109/L and 200 x 109/L. Patients who achieved at least stable disease at the end of cycle 6 and who had, in the investigator's opinion, a clinical ben- efit were eligible to continue ruxolitinib (15 mg or 20 mg), which was defined as “maintenance” therapy. Treatment could be contin- ued for up to 2 years or until progressive disease, intolerability, or as long as the investigator thought that there was clinical benefit.
Administration of the study drug could be stopped for any grade ≥3 non-hematologic toxicity, with the exception of deep venous thrombosis and alopecia. Following event resolution to grade ≤1, ruxolitinib could be resumed, with a 5 mg dose reduction and a maximum delay of 4 weeks. Mandatory dose decreases or inter- ruptions for hematologic toxicity as well as the rules for perma- nent discontinuation are detailed in the Online Supplementary Appendix. Growth factors were allowed as per American Society of Clinical Oncology guidelines and infectious prophylaxis as per the guidelines of Heine et al.21
haematologica | 2018; 103(5)
Ruxolitinib in advanced relapsed/refractory HL
841