P1038: tl-895, a first-in-class, covalent bruton tyrosine kinase inhibitor (btki) for the treatment of myelofibrosis (mf) patients (pts) with severe thrombocytopenia (platelets (plts) <50 k/ul)

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Nearly 35% of MF pts have severe thrombocytopenia (TCP) with a shortened median overall survival of 7-15 months (mos) (Masarova 2018, 2020). Most pts present with high symptom burden due to dysregulated cytokines (Tefferi 2011), of which elevated IL-8 impairs megakaryocyte function (Emadi 2005). Treatment with JAK inhibitors (JAKi) can worsen TCP in MF pts, with no effective therapies to improve plt counts. TL-895 is a highly potent, selective, orally available, small molecule inhibitor of BTK and bone marrow tyrosine kinase X-linked (BMX) being studied in MF for its potential to (i) impair stromal adhesion, (ii) disrupt aberrant CD34+ cell trafficking (Nimmagadda 2019), (iii) reduce proinflammatory cytokine-mediated symptoms, and (iv) reverse dysfunctional megakaryopoiesis to improve plt counts. Aims: Safety, efficacy, and tolerability of TL-895 in MF pts with severe TCP. Methods: Cohort 3 of this open-label, global Phase (Ph) 2 study (NCT04640532) enrolled adult pts with JAKi-ineligible MF (plts <50 K/μL, ≥25 K/μL). Pts were randomized to TL-895 150 mg BID (Arm A) or 300 mg QD (Arm B). Eligible pts were symptomatic with intermediate/high-risk MF (DIPSS), ECOG £2 with splenomegaly. The primary objective was the recommended Ph 2 dose (RP2D). Key secondary objectives were Total Symptom Score improvement ³50% by MFSAF v4.0 at Week (Wk) 24 (TSS-50), spleen volume reduction ³35% at Wk 24 by central review (SVR-35) and safety. Plt response was assessed per modified IWG-MRT 2006 criteria (plt increase ≥50% from baseline and >50 K/μL for ≥8 wks independent of plt transfusion [Tefferi 2006]). Results: As of 27 Jan 2022, 11 pts were enrolled in Arm A and five pts in Arm B with median follow-up of 11.7 mos. Complete BTK occupancy (≥95%) was achieved in Arm A at trough (C1D8), but not Arm B which closed early. Arm A is described herein. In these 11 pts, baseline median plt count was 39 K/μL, median spleen volume was 1908 cm3, median TSS was 24.7, and 73% were previously treated with a JAKi (Table 1). Six pts (55%) remain on study and five discontinued due to Grade (Gr) 3 fatigue (n=1), progression (n=2) and investigator decision (n=2). Ten (91%) pts were alive at data cut (median 12.4 mos). At Wk 24, four pts (36%) achieved TSS-50 (Fig. 1), despite no pts achieving SVR-35 (median SVR -5.3%, range -18, 38)). Per modified IWG-MRT criteria, five pts (45%) achieved plt response (≥50% improvement for ≥8 weeks [Fig. 2]), two pts (18%) achieved ≥100% plt improvement with a third pending 8-week confirmation (27%). Median time to plt response was 2.9 mos; median duration was 6.7 mos (range 1.9, 13.1+). Median change in serum IL-8 levels from baseline to Wk 12 was -38% and was associated with plt and TSS response. Median change in circulating CD34+ cells from baseline to Wk 4 was +85%, demonstrating transient cell trafficking due to BTK inhibition. The most common treatment-emergent adverse events were anemia (55%), abdominal pain, nausea and TCP (27% each). Anemia and TCP were the most common Gr 3/4 AEs, regardless of causality, 46% and 27%, respectively (Table 1). Summary/Conclusion: In MF pts with severe TCP, TL-895 provided clinically meaningful improvements in TSS and plt counts that were associated with reductions in IL-8. This is the first clinical proof-of-concept for BTKi in the treatment of MF and supports further investigation in a recently commenced randomized, double blind, placebo-controlled Ph 2b study.Keywords: Thrombocytopenia, IL-8, Myelofibrosis, Bone Marrow Fibrosis