Contributions
Abstract: S492
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 16:15 - 16:30
Location: Room N103
Background
There are no approved therapies for chronic GVHD (cGVHD) after failure of steroids. Both B and T cells play a role in the pathophysiology of cGVHD. In preclinical models, ibrutinib (ibr) reduced the severity of cGVHD through inhibition of Bruton’s tyrosine kinase (BTK) and interleukin-2–inducible T-cell kinase (ITK).
Aims
This phase 2 study evaluated the efficacy and safety of ibr in patients (pts) with steroid dependent/refractory cGVHD in need of additional therapy.
Methods
Eligible pts had ≤3 prior regimens for cGVHD and either >25% body surface area erythematous rash or a NIH mouth score >4. Informed consent was obtained from all pts. Pts were treated with ibr 420 mg/d until cGVHD progression or unacceptable toxicity. The primary end point was cGVHD response based on 2005 NIH consensus response criteria. Secondary end points included rate of sustained response, change in Lee cGVHD symptom scale, change in steroid dose over time, and safety. The pharmacodynamics (PD) of ibr and its effects on biomarkers associated with GHVD, inflammation, and fibrosis were evaluated.
Results
A recommended phase 2 dose of 420 mg was identified in phase 1b (n=6). For 42 pts in phase 2, the median number of prior cGVHD regimens was 2 (range, 1–3). At a median follow-up of 13.9 mo, overall response rate (ORR) was 67% (CR, 21%), with 71% of responders showing a sustained response of ≥20 weeks; 79% responded by the first response assessment. Median steroid dose decreased in responders from 0.29 mg/kg/d at baseline to 0.12 mg/kg/d at week 49. Overall, 62% of pts achieved steroid doses <0.15 mg/kg/d while on ibr; 5 responders discontinued steroids. Organs with cGVHD involvement including skin, mouth, and gastrointestinal system showed similar responses (~90%). Of 25 responders with ≥2 involved organs, 20 (80%) showed a response in ≥2 organs. Improvement in Lee cGVHD symptom score was reported for 43% of responders by month 6 and 61% overall, compared with 11% of nonresponders by month 6 and overall. Ibr blocked BTK-driven basophil activation in an ex vivo IgE stimulation assay and ITK-mediated activation of PLCγ1-Y783 in CD4 T-cells. Analysis of soluble plasma factors associated with inflammation, fibrosis, and cGVHD from all treated pts showed a significant decrease over time with ibr. Adverse events (AEs) were largely grade 1 or 2 events; AEs occurring in ≥20% of pts were fatigue, diarrhea, muscle spasms, nausea, and bruising. Grade ≥3 AEs occurring in ≥10% of pts were pneumonia, fatigue, and diarrhea. Serious AEs (SAEs) occurred in 52% of pts; grade ≥3 SAEs were reported in 40% of pts and included pneumonia, septic shock, and pyrexia. Two fatal events (multilobular pneumonia and bronchopulmonary aspergillosis) were reported. Fourteen pts discontinued ibr for AEs, 5 pts for progressive cGVHD, and 2 pts after resolution of cGVHD symptoms; 29% continued ibr.
Conclusion
With an ORR of 67% and a sustained response rate of ≥20 weeks of 71%, treatment with ibr resulted in clinically meaningful and durable responses in pts who failed at least 1 prior treatment for cGVHD. Most responders were able to reduce steroid dose. PD and biomarker changes support a beneficial effect of ibr on immune cell subsets in pts with cGVHD. The safety profile was consistent with those previously reported for pts with B cell malignancies and those seen in cGVHD pts on concomitant steroids. Responses in this pretreated, high-risk population support study of ibr for frontline treatment of cGVHD.
Session topic: 22. Stem cell transplantation - Clinical
Abstract: S492
Type: Oral Presentation
Presentation during EHA22: On Saturday, June 24, 2017 from 16:15 - 16:30
Location: Room N103
Background
There are no approved therapies for chronic GVHD (cGVHD) after failure of steroids. Both B and T cells play a role in the pathophysiology of cGVHD. In preclinical models, ibrutinib (ibr) reduced the severity of cGVHD through inhibition of Bruton’s tyrosine kinase (BTK) and interleukin-2–inducible T-cell kinase (ITK).
Aims
This phase 2 study evaluated the efficacy and safety of ibr in patients (pts) with steroid dependent/refractory cGVHD in need of additional therapy.
Methods
Eligible pts had ≤3 prior regimens for cGVHD and either >25% body surface area erythematous rash or a NIH mouth score >4. Informed consent was obtained from all pts. Pts were treated with ibr 420 mg/d until cGVHD progression or unacceptable toxicity. The primary end point was cGVHD response based on 2005 NIH consensus response criteria. Secondary end points included rate of sustained response, change in Lee cGVHD symptom scale, change in steroid dose over time, and safety. The pharmacodynamics (PD) of ibr and its effects on biomarkers associated with GHVD, inflammation, and fibrosis were evaluated.
Results
A recommended phase 2 dose of 420 mg was identified in phase 1b (n=6). For 42 pts in phase 2, the median number of prior cGVHD regimens was 2 (range, 1–3). At a median follow-up of 13.9 mo, overall response rate (ORR) was 67% (CR, 21%), with 71% of responders showing a sustained response of ≥20 weeks; 79% responded by the first response assessment. Median steroid dose decreased in responders from 0.29 mg/kg/d at baseline to 0.12 mg/kg/d at week 49. Overall, 62% of pts achieved steroid doses <0.15 mg/kg/d while on ibr; 5 responders discontinued steroids. Organs with cGVHD involvement including skin, mouth, and gastrointestinal system showed similar responses (~90%). Of 25 responders with ≥2 involved organs, 20 (80%) showed a response in ≥2 organs. Improvement in Lee cGVHD symptom score was reported for 43% of responders by month 6 and 61% overall, compared with 11% of nonresponders by month 6 and overall. Ibr blocked BTK-driven basophil activation in an ex vivo IgE stimulation assay and ITK-mediated activation of PLCγ1-Y783 in CD4 T-cells. Analysis of soluble plasma factors associated with inflammation, fibrosis, and cGVHD from all treated pts showed a significant decrease over time with ibr. Adverse events (AEs) were largely grade 1 or 2 events; AEs occurring in ≥20% of pts were fatigue, diarrhea, muscle spasms, nausea, and bruising. Grade ≥3 AEs occurring in ≥10% of pts were pneumonia, fatigue, and diarrhea. Serious AEs (SAEs) occurred in 52% of pts; grade ≥3 SAEs were reported in 40% of pts and included pneumonia, septic shock, and pyrexia. Two fatal events (multilobular pneumonia and bronchopulmonary aspergillosis) were reported. Fourteen pts discontinued ibr for AEs, 5 pts for progressive cGVHD, and 2 pts after resolution of cGVHD symptoms; 29% continued ibr.
Conclusion
With an ORR of 67% and a sustained response rate of ≥20 weeks of 71%, treatment with ibr resulted in clinically meaningful and durable responses in pts who failed at least 1 prior treatment for cGVHD. Most responders were able to reduce steroid dose. PD and biomarker changes support a beneficial effect of ibr on immune cell subsets in pts with cGVHD. The safety profile was consistent with those previously reported for pts with B cell malignancies and those seen in cGVHD pts on concomitant steroids. Responses in this pretreated, high-risk population support study of ibr for frontline treatment of cGVHD.
Session topic: 22. Stem cell transplantation - Clinical