Final Results from a Phase 4 Open-Label 3-Year Study Evaluating Changes in Bone Marrow (Bm) Morphology in Adult Immune Thrombocytopenia (ITP) Patients (Pts) Receiving the Thrombopoietin Mimetic Romiplostim

Introduction: Normal bm may contain reticulin, which is of unknown clinical relevance. An analysis of romiplostim ITP trials as of 2011 showed 17 reticulin cases and one collagen case; however, biopsies were not performed systematically. Reported here are final results from a prospective 3-year (y) study evaluating bm biopsies for reticulin and collagen before and after treatment with romiplostim in adult ITP pts.

Methods: Eligible ITP pts had platelets <50x10⁹/L, received ≥1 prior ITP therapy, and had no collagen in baseline bm biopsies (before romiplostim). Biopsies were scheduled after 1 (Cohort 1), 2 (Cohort 2), or 3 (Cohort 3) y of romiplostim, dosed to maintain platelets at 50–200x10⁹/L; all cohorts could receive 3 y of romiplostim. Biopsies were also performed if pts discontinued early or failed to achieve/maintain a response to romiplostim (platelets ≤20x10⁹/L for 4 consecutive weeks at the max dose of 10 µg/kg). Reticulin and collagen were evaluated using the modified Bauermeister scale (0 no reticulin; 1 occasional fine fibers/foci of fine fiber network; 2 fine fiber network; 3 diffuse fiber network, scattered coarse fibers; 4 diffuse coarse fiber network, areas of collagenization). Collagen was detected by trichrome staining and reticulin by silver staining. Two hematopathologists at a central laboratory read all the samples; an independent panel reviewed grading discrepancies.

Results: All pts received romiplostim and had evaluable baseline bm biopsies. Of the 50 pts in Cohort 1 [54% female, mean age 55.5 y, range 20–86 y, mean (SD) dose 4.0 (2.8) µg/kg], 39 had post-baseline bm biopsies (Table). No pts with evaluable results developed collagen or had an increase ≥2 grades from baseline in reticulin. Of the 50 pts in Cohort 2 [76% female, mean age 48.6 y, range 19–83 y, mean (SD) dose 4.3 (3.1) µg/kg], 40 had post-baseline bm biopsies. There was no evidence of collagen; 2 pts had a 2-grade increase in reticulin. Of the 69 pts in Cohort 3 [71% female, mean age 46.6 y, range 18-81 y, mean (SD) dose 4.1 (2.9) µg/kg], 58 had post-baseline bm biopsies; 7 pts had a 2-grade increase in modified Bauermeister score, with 2 of the 7 showing collagen. Of those 2, 1 had no evidence of collagen on follow-up biopsy 12 weeks later; the other refused a follow-up biopsy.

The safety profile was similar to that in past trials. In Cohort 1, 4 pts died; causes were fungal sepsis in a pt with longstanding corticosteroid use, cerebral hemorrhage, pulmonary hemorrhage in a pt with pulmonary thrombosis treated with acenocoumarol, and subdural hematoma that occurred after the pt fell and sustained a head injury. In Cohort 2, 2 pts died; causes were acute renal failure in a pt with a history of chronic renal insufficiency and suicide. In Cohort 3, 1 pt died of multiple thromboses of microcirculation and failure of the heart, kidneys, and lungs. No deaths were attributed to romiplostim. One pt in Cohort 3 tested positive for neutralizing antibodies (Ab) to romiplostim at Week 30 through the Year 1 visit, but was Ab negative on a subsequent test; the last romiplostim dose was at Week 36, but the pt maintained platelet response throughout.

Summary/Conclusion: An increase in modified Bauermeister score by ≥2 grades occurred in 9 of 131 pts (6.9%) treated with romiplostim; 7 had increased reticulin only and 2 also had collagen. The low incidence of both collagen and increased reticulin is consistent with results of past romiplostim studies.

Table Biopsy Results

¹ 3 pts in cohort 1, 3 in cohort 2, and 10 in cohort 3 had biopsies at end of treatment due to early discontinuation.

² Trichrome and silver staining results could not be obtained for all biopsies due to inadequate samples.

³ Duration-adjusted, per 100 pt-y

⁴ 1 case: grade 0 to 2; 1 case: grade 1 to 3

⁵ 1 case: grade 4 after 25 weeks in a pt with atypical ITP, no evidence of collagen on follow-up biopsy 12 weeks later; 1 case: grade 4 at end of treatment, pt refused follow-up biopsy

⁶ 2 cases: collagen (as above in ⁵); 2 cases: grade 0 to 2; 3 cases: grade 1 to 3