PURPOSE:
Over-activation of TGF-b signaling is observed in myelodysplastic syndromes myelodysplastic syndromes: (my-eh-lo-diss-PLASS-tik SIN-dromez) A group of disorders where the bone marrow does not work well, and the bone marrow cells fail to make enough healthy blood cells. Myelo refers to the bone marrow. Dysplastic means abnormal growth or development. People with MDS have low blood cell count for at… and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-b receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of myelodysplastic syndromes (MDS) and acceptable toxicity in phase 1 studies of solid malignancies.
EXPERIMENTAL DESIGN:
A Phase 2 multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the IPSS-R criteria with hemoglobin hemoglobin: A protein in the red blood cells. Hemoglobin picks up oxygen in the lungs and brings it to cells in all parts of the body. ≤10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off.
RESULTS:
Ten of 41 evaluable patients (24.4%, 95% CI: 12.4, 40.3) achieved hematologic improvement erythroid response by IWG 2006 criteria. 18/41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. 9/28 (32.1%) of transfusion-dependent patients had hematologic improvement. 18/41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry flow cytometry: (sy-TOM-uh-tree) A laboratory test that gives information about cells, such as size, shape, and percentage of live cells. Flow cytometry is the test doctors use to see if there are any proteins missing from the surface of blood cells. It is the standard test for confirming a diagnosis of paroxysmal… showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%).
CONCLUSIONS:
In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block. ClinicalTrials.gov, number NCT02008318.