Ruxolitinib in Combination with Orally Etoposide and Corticosteroids (REC) Is Safe and Effective in Heavily Pretreated Hodgkin and Non-Hodgkin Lymphomas

Purpose

The JAK/STAT pathway is deregulated in Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBL) (Scott et al, 2015; Younes et al, 2014; Shipp et al, 2010). In Diffuse large B cell lymphoma (DLBCL), especially in ABC subtype, the LP265 mutation of the MYD88 gene enhances IL6 and IL10 secretion by the microenvironment permitting the activation of the JAK/STAT pathway. (Gandhi et al, 2015). The overexpression of JAK2 stimulates the phosphorylation of STAT3 in DLBCL and STAT6 in PMBL with a subsequent activation of target genes of the NFKB signaling pathway. Therapeutic inhibition of JAK2 decreases the growth of lymphoid tumors in vitro and in murine xenograft models. (Hao et al, 2014).

Although Younes et al reported response in 3 of 15 patients with refractory or relapsed (R/R) follicular or mantle cell lymphoma who received pacritinib alone, no data are available on the effect of ruxolitinib (Jakavi®), the first approved JAK1/JAK2 inhibitor, in lymphoma patients.  

Here we report the effect and safety of the oral combination of continuous Ruxolitinib, Etoposide and Corticosteroids in patients with R/R lymphoma.

Patients and Methods

Since December 2014, patients with multirefractory/relapsed DLBCL, HL or plasmablastic lymphoma received Ruxolitinib 10mg X 2 or 5mg X 2 daily (in case of neutropenia < 1000/mm3) and oral Etoposide 50mg/m2 with prednisone 0,5 mg/kg daily. Retrospective immunostaining (IS) of phosphostat3 (pSTAT3) and phosphostat5 (pSTAT5) was performed on diagnostic samples. In these patients the response rate (including stable disease) was estimated ≤ 0,10 (null hypothesis). In order to identify a potentially relevant clinical activity in these patients with very poor prognosis, the alternative hypothesis was defined by a response rate ≥ 0,500. According to an optimal 2-Stage Designs for Phase II Clinical Trials, a total of 9 patients have to be enrolled in case of response (or stable disease) in at least 1 of the 3 first patients. All patients gave informed consent.

Results

Six patients (DLBCL: 4, HL: 1, plasmablastic lymphoma: 1) were treated between December 2014 and May 2015. All patients had a progressive disease before starting REC. Median age was 57,5 years (range 30-87). DLBCL Phenotype was non Germinal Center (non-GC) in 2 patients and Germinal Center (GC) in 1 patient. One patient had received autologous stem cell transplantation (ASCT) and one allogenic (HSCT); 3 months later he developed a severe macrophagic activation syndrome (MAS).  Median prior treatment was 5 (range 1-12). Four of six patients had a response: 1 partial response (PR) and 3 stable disease (SD) (including control of MAS for 3 months). Two patients had a disease progression (PD). Progression-free survival (PFS) was 82.5 days (range 30-129). There were no side effects reported and only one day hospitalization for transfusion (Table 1). Immunostaining showed expression of pSTAT3 and pSTAT5 on tumoral cells but not in the microenvironment. There was a higher level of pSTAT3 expression (range 0-70%) compared with expression of pSTAT5 (range 0-50%); both were not predictive of the treatment response. (Table 1)

Conclusion

REC is the first orally combination with Ruxolitinib reported to our knowledge in R/R lymphoma patients. Stable disease or PR has been achieved without toxicity in the first 6 patients with poor prognosis lymphoma. These preliminary results of this ongoing trial suggest that Ruxolitinib chemotherapy combination may be a promising approach for R/R HL or DLBCL lymphoma patients. Biological analysis of the JAK/STAT “signature” including expression of pSTAT3 and pSTAT5 and mutations of activating genes like MYD 88 and SOCS-1 will be presented at the ASH meeting.

 

Patient	Age	Lymphoma subtype	IPI score	pSTAT3 IS (%)	pSTAT5 IS (%)	N° of prior therapies	Ruxolitinib Dose	Response	PFS (day)	Toxicity
1	34	DLBCL GC	3	0	0	6 (RCHOP, DHAP, IVAM, HSCT,VP16, Holoxan)	10mg X 2/d	SD	82	0
2	48	Plasmablastic	2	30	1	7(RACVBP/ HoloxanVP16, CYVE,PAD, Gemcitabine,Vidaza,Revlimid,RT)	5mg X 2/d	SD	83	0
3	87	DLBCL	2	20	10	1 (RminiCHVP)	5mgx 2/d	PR	129	Anemia Grade 2
4	35	HL		50	50	12 (RCHOP, BEACOPP, ESHAP,RT, BEAM ASCT, SGN35, Bendamustine,methotrexate/L-asparaginase, Caelyx, everolimus, Navelbine, Revlimid)	10mg X2/d	SD	102	0
5	67	DLBCL non-GC	3	30	1	4 (Fludarabine, Endoxan, RCHOP, DHAP)	5mgX2/jour	PD	30	0
6	74	DLBCL non-GC	2	70	1	3 (MBVP, ARA-C, RT)	5mgx 2/d	PD	75	0

Table1: Characteristics of the 6 patients. ( RT: radiotherapy)