Single Centre, Retrospective Study to Evaluate Treatment Outcomes Following Tyrosine Kinase Inhibitor for Chronic Gvhd Treatment Including Ruxolitinib, Ibrutinib and Imatinib
Authors: Linn Swe Mar , Abduljalil Omar , Novitzky-Basso Igor Nicolas , Nampoothiri RAM V , Pasic Ivan , Al-Shaibani Zeyad , Lam Wilson , Law Arjun , Michelis Fotios , Gerbitz Armin , Viswabandya Auro , Lipton Jeffrey H. , Kumar Rajat , Mattson Jonas , Kim Dennis Dong Hwan 
Published: February 2021

Background
Chronic graft-versus-host-disease (cGVHD) is one of the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT). Tyrosine kinase inhibitor such as Ruxolitinib, Ibrutinib and Imatinib showed a promising efficacy in cGVHD treatment. Ruxolitinib is a JAK-STAT inhibitor, reducing inflammation and immune pathway. Ibrutinib is a BTK inhibitor, blocking B cell-activating factor (BAFF), while Imatinib inhibits the platelet-derived growth factor receptor pathway activated by cGvHD-induced antibodies.
The present retrospective study evaluated the efficacy of 3 TKIs for cGVHD at a single-centre in terms of 1) overall response rate (ORR), 2) clinical benefit (CB), 3) dose reduction of steroid, 4) failure-free survival (FFS) and 5) overall survival (OS).
Patients and Methods
A total of 43 patients who developed cGVHD after HCT and treated with TKI therapy for cGVHD at Princess Margaret Cancer Centre, Canada from August 2014 to April 2020 were evaluated in this retrospective study. 16 patients were treated with more than one TKI drug. A total of 62 lines of TKI therapy was evaluated, including Ruxolinitib (n=18), Ibrutinib (n=13) and Imatinib (n=31).
The ORRs and CBs were assessed at months 3, 6 and 12, retrospectively. Responses were evaluated according to NIH scoring/staging/response assessment as part of standard clinical practice. CB was assessed considering clinical response as well as steroid dose reduction. For systemic steroid dose reduction, prednisone dose per kg per day was captured prior to Ruxolitinib start, at months 3, 6 and 12.
Treatment failure was defined as 1) resistance requiring treatment switch, 2) non-relapse mortality (NRM), 3) relapse, 4) intolerance requiring treatment discontinuation. FFS and OS were calculated from the day of starting TKI therapy for cGVHD treatment.
Results
The patients and disease characteristics are summarized as follow: median age was 54 years (range 16 -70); 33 patients (53%) presented with classical cGVHD, while 29 patients (47%) with overlap syndrome; 14 (23%) presented with moderate and 48 (77%) with severe grade cGVHD. There was no difference in cGVHD subtype among 3 TKI subgroups (p= 0.478).
The median number of organ involvement was 3 (range 1-5), and number of previous lines of therapy was 5 (range 3-9), implying that most of the patients were heavily pretreated for cGVHD.
The mean (±S.E.) dosage of TKI treatment was as follows: Ruxolitinib was started at 15±1.1mg as initial dose and 20±0.7, 19±1.5, 22±4.4 mg per day in two divided doses on months 3, 6 and 12, respectively. Ibrutinib dose was 226±37, 256±37, 308±40 and 370±33 mg per day, while Imatinib dose was 106±6, 189±18, 196±16 and 190±19 mg per day prior to TKI starts, at months 3, 6 and 12, respectively.
With a median follow up duration of 12 months, 19 (31%), 20 (32%), and 17 patients (27%) responded to TKI therapy at 3, 6, and 12 months without any difference of ORR among the TKIs (p=0.126, 0.554, 0.721 at 3/6/12 months; Figure A). The CBs were achieved in 47 (76%), 34 (55%), and 23 patients (37%) at 3, 6 and 12 months without any difference of CBs among the TKIs (p=0.187, 0.499, 0.750 at 3/6/12 months; Figure B).
Prednisone dose (mg/kg/day) was 0.238±0.03 prior to TKI initiation, 0.177±0.03, 0.173 ± 0.03 and 0.110 ± 0.02 at 3, 6, and 12 months, respectively. No difference was noted in steroid dose among the 3 TKIs at each time point. However, the Ibrutinib group tends to require higher prednisone dose over time than other 2 groups.
The FFS at 12 months was higher in Imatinib (71%) or Ruxolitinib groups (67%) than Ibrutinib group (46%; Figure C). The OS rate at 12 months was similar: 100 % in Ruxolitinib and Ibrutinib, and 96% in Imatinib group (Figure D).
With regard to those patients treated with TKI for sclerotic GVHD (n= 39), the ORR were 11 (28%), 15 (38%) and 13 (33%) for 3, 6 and 12 months, while CB was noted in 32 (82%), 25 (64%) and 16 patients (41%) at 3, 6 and 12 months respectively. Of interest, Ruxolitinib was as effective as Imatinib in improving PROM score of sclerotic GVHD, while no significant improvement of PROM score was observed in the patients treated with Ibrutinib.
Conclusion
This retrospective study evaluated the efficacy of TKI drugs for cGVHD treatment in heavily pretreated patients. Ruxolitinib seems as effective as Imatinib to treat sclerotic GVHD. No difference was observed in OS at 12 months; while FFS appears better with Ruxolitinib and Imatinib over Ibrutinib.
Figure

Disclosures
Lipton: Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding.