Hematologic Improvement (HI) by TLK199 (Telintra™), a Novel Glutathione Analog, in Myelodysplastic Syndrome: Phase 2 Study Results.

Introduction: Glutathione S-transferase (GST) P1-1 has shown to be an important negative regulator of cellular growth and differentiation. The effect is mediated through binding to Jun kinase (JNK) which causes a decrease in kinase activity. TLK199, a novel analog of glutathione, binds selectively to GSTP1-1 resulting in its dissociation from JNK and subsequent kinase activation. Exposure of hematopoietic progenitor cells to TLK199 led to activation of JNK followed by cellular growth and maturation. TLK199 has shown significant myelostimulant activity in vitro in human bone marrow cell cultures as well as in several in vivo preclinical models of myelopoeisis. In Phase 1, TLK199 treatment resulted in hematologic improvement (HI) in MDS patients at all dose levels.

Methods: The objectives of this multicenter Phase 2 study in MDS were to determine the safety (by NCI-CTC) and efficacy (by modified IWG MDS response criteria) of two dose schedules of TLK199 HCl Liposomes for Injection administered at 600 mg/m² over 60 minutes by constant rate IV infusion daily x 3 or daily x 5 every 3 weeks. Patients (pts) were treated until lack of response or unacceptable toxicity.

Results: 52 MDS pts (33 M/19 F),(29 RA, 9 RARS, 8 RAEB, 3 RAEB-t, 1 CMML, 2 UK), median age 69 years (range 22–90), received 244+ cycles (1099+ treatments), median 4 (range 1–13+). Thirty-seven pts (71%) were red cell transfusion dependent and 10 pts (19%) were platelet transfusion dependent prior to entry. Pts had failed a median of 1 prior therapy (range 0–6) including: erythropoietin (27/52%), G-CSF (9/17%), thalidomide (10/19%), azacitidine (7/14%), steroids (6/12%), hormones (2/4%), and other therapies (14/27%). Thirty-nine pts were evaluable for efficacy, 32 pts (82%) experienced HI in one or more blood cell lineages, 14 of 16 pts (88%) with trilineage dysfunction, 8 of 13 pts (62%) with bilineage dysfunction, and all 10 pts (100%) with unilineage dysfunction experienced HI. Lineage response was HI-P (14 of 22/64%), HI-N (9 of 27/33%), and HI-E (22 of 35/63%). Responses were accompanied by clinical symptom improvement, decreases in RBC and platelet transfusion requirements including transfusion independence and improvements in bone marrow maturation, differentiation, M/E ratios, and dysplastic morphology. Most common adverse events were mild to moderate acute infusion related reactions commonly seen with liposomal formulations: back pain (9/17%), nausea (8/15%), chills (8/15%), and bone pain (6/12%).

Conclusions: TLK199 is well tolerated and an active agent in all FAB types of MDS. These data support the further clinical development of TLK199 in MDS as well as in other hematologic malignancies characterized by cytopenias.