Preliminary Study On Ruxolitinib In The Salvage Treatment Of Refractory Pulmonary Chronic Graft-Versus-Host Disease(Bronchiolitis Obliterans Syndrome)

Objective Allogeneic hematopoietic stem cell transplantation(Allo-HSCT)is a radical treatment for malignant and non-malignant hematological diseases.However,30%-70% of patients will develop chronic graft-versus-host disease(c GVHD),of which bronchiolitis obliterans syndrome(BOS)is a severe pulmonary c GVHD,which seriously affects the long-term survival and quality of life of patients.Refractory patients who fail to respond to traditional first-line and second-line drugs has a high mortality rate.Janus kinase / signal transduction and activator of transcription(JAK-STAT)signaling pathway plays an important role in the occurrence and development of c GVHD.Ruxolitinib is the selectivity of JAK1/2 equivalent inhibitors and has been shown to be safe and effective in mouse GVHD models and in many human GVHD clinical studies.The purpose of this article is to explore the efficacy of salvage in the treatment of patients with refractory BOS.Methods A retrospective analysis of 10 patients with refractory BOS diagnosed in our center from September 2017 to June 2019 and have failed to respond to anti-c GVHD first-line or/and second-line drugs.Salvage treatment regimen is consisted of Ruxolitinib(2.5mg/bid if weight <25kg;5mg/bid if weight ?25kg),glucocorticoid(12mg/qd),FAM(inhaled budesonide 1-2mg/bid,azithromycin 0.25g/qod,montelukast 10mg/qn)and prevention of infection(azole antifungal drugs,compound sulfamethoxazole 0.48 g,bid/biw,acyclovir 0.2g tid).Diagnosis and evaluation of the disease before and during treatment [divided into symptoms and signs score and pulmonary function testing(PFT)score] To evaluate the clinical efficacy,PFT stability,drug safety and survival of patients.Results There were 7 males and 3 females in this group,with a median age of 15(11-56)years.The median time from HSCT to the onset of pulmonary symptoms and signs was 7(3-13)months.The median time from diagnosis by PFT from HSCT was 9(5-24)months.The median duration of pulmonary symptoms and signs to diagnosis by PFT was 2(1-13)months.Symptoms and signs include: 7 cases of dry cough,2 cases of fever,10 cases of shortness of breath and wheezing after exercise or resting(6 after walking on the plat ground,2 after climbing steps and 2 at rest).According to the 2015 National Institute of Health(NIH)c GVHD diagnosis and scoring standards,lung symptom and signs-based scores were as follows: 6 cases of 1 point,2 cases of 2 points,and 2 cases of 3 points.The median time from the onset of symptoms to the first time of pulmonary function test(PFT)was 2(1-12)months.The average Forced Expiratory Volume in the first second rate(FEV1%)of the first PFT was 50.5(29-76)%.FEV1%-based scores were as follows: 2 cases of 1 point,5 cases of 2 points and 3cases of 3 points.NIH Global Severity of c GVHD: 2 cases of moderate and 8 cases of severe.The median time to take Ruxolitinib was 4(1-15)months.The median time to improvement of wheezing and dry cough was 2(1-4)weeks.FEV1% recovered slowly,but maintained at a stable level.Two patients had complete response(CR)after 1 month and the symptoms completely disappeared and FEV1% reached to normal.Partial response(PR)was obtained in 8 cases with the FEV 1% value increased by more than10% in 4 cases and the pulmonary symptom score decreased by 1 or more in 4 cases.All patients were alive until the last follow-up,with a median follow-up time of 13(8-29)months.None of them progressed.Two patients had recurrence of the primary disease 10 and 4 months after Ruxolitinib discontinuation.The one-year relapse-free survival rate was 80%.They had been alleviated after interferon treatment and chemotherapy.All patients were well tolerated and had no serious side effects.Conclusion 1.Clinicians should pay close attention to the patient's lung history after Allo-HSCT.Patients with recurrent fever with pulmonary infection,dry cough,wheezing and dyspnea after exercise,should undergo imaging examinations and timely monitoring of PFT to improve the awareness and early diagnosis of BOS.2.Ruxolitinib is safe and effective for salvage treatment of patients with refractory BOS.It is expected to be a second-line drug treatment for patients with BOS.