Background: Graft-versus-Host Disease (GVHD) is a complication that occurs in 30-70% of hematologic malignancy patients post-hematopoietic stem cell transplant (HCT) (Flowers, February 2021). Steroid refractory GVHD has led to studies approving ruxolitinib and ibrutinib as the first FDA approved therapies for steroid refractory GVHD. Ruxolitinib is approved to treat acute GVHD (aGVHD) and inhibits Janus associated kinase (JAK). Ibrutinib is approved to treat chronic GVHD (cGVHD) and functions by inhibiting Bruton's tyrosine kinase (BTK). Here we describe 2 cases of patients who received both drugs for their GVHD.
Patient #1 was a 4-year-old female who had a diagnosis of NK cell dysfunction. The patient underwent a conditioning regimen with melphalan 140 mg/m2, fludarabine 30 mg/m2 X5, and alemtuzumab for 5 days. The allogeneic HCT was performed with cells from a 9/10 NMDP donor and received a CD34+ enrichment with T cell addback of 2.1 x10^5 CD3/kg. Tacrolimus was given for GVHD prophylaxis. The patient developed aGVHD stage 2, grade 3 of the gut on day +148. Patient received steroids, extracorporeal photopheresis (ECP), and cellcept, and the GVHD resolved. The patient then developed skin GVHD on day +189 (stage 1, grade 3) that resolved. Approximately 15 months post-transplant there was concern the patient was developing cGVHD of the skin and gut (chronic though stable diarrhea), and therefore ibrutinib was initiated day +490 at 140 mg daily. The cGVHD persisted despite ibrutinib, ECP, tacrolimus, and sirolimus. Ruxolitinib was then initiated 2.5 mg bid on day +883. Patient demonstrated stable to slightly improved GVHD and tapered ibrutinib to 110 mg between days +951 and +980. The patient remained on ruxolitnib and ibrutinib as of day +1172.
Patient #2 was a 1-year-old male with sickle cell anemia. The patient was transplanted under a haploidentical protocol from the mother, receiving a CD34+ enrichment with T cell addback of 2x10^5 CD3/kg. The conditioning regimen was busulfan 2 mg/kg, fludarabine 30 mg/m2, cyclophosphamide 50 mg/kg, and thymoglobulin 2 mg/kg with tacrolimus as GVHD prophylaxis. Patient was experiencing fevers, dyspnea and CT was concerning for an infiltrative process. Broad spectrum antibiotics did not improve symptoms. A lung biopsy was performed and bronchiolitis obliterans organizing pneumonia (BOOP) was diagnosed on day +217 (pathology confirmed GVHD). The pathology report was reviewed at an outside institution, raising the question of thrombotic microangiopathy (TMA) in context of hemolysis markers (high LDH and low platelets). Patient was placed on Fluticasone, Azithromycin, and Montelukast (FAM). Due to persisting BOOP confirmed on lung biopsy on day +407, the patient started ibrutinib 140 mg daily on day +411 and was started on ruxolitinib 2.5 mg bid on day +412. ECP commenced on day +414. Within 1 month, symptoms improved. Lung CT imaging appeared stable since initiation of these modalities. Patient continued with ruxolitinib, ibrutinib and ECP (twice per week) for GVHD, though the ruxolitinib dose was tapered in half starting day +477. Symptoms have improved.
Discussion: To our knowledge this is the first reported case series of concomitant use of ruxolitinib and ibrutinib. A literature search (PubMed and abstracts in society meetings) was conducted that found 1 paper focused on ruxolitinib for cGVHD with 3 patients on concomitant ibrutinib, but without further details (Ferreira et al., June 2021). Our cases represent a proof-of-concept approach to GVHD management and demonstrate the feasibility of administrating both agents. The combination was well-tolerated with no significant adverse events noted. Neither patient had to discontinue due to poor tolerance or interactions. We expect this dual-drug therapy will become more common going forward given FDA approvals for both ruxolitinib and ibrutinib. Recently, ruxolitinib underwent a successful trial for glucocorticoid-refractory cGVHD when compared to best available therapies, including ibrutinib, though the drugs were not tested in combination (Zeiser et al., July 2021). These findings may open the door for further concomitant use, especially if ruxolitinib is approved by the FDA for cGVHD. We propose further investigation into dual therapy of these drugs in cGVHD either compared to steroids or as a second line option.
Disclosures
Cairo: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees.
OffLabel Disclosure:
Ruxolitinib is being used here for chronic GVHD, while it is FDA approved for acute GVHD.
