Abstract Background: Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder marked by significant inflammation and immune deregulation, that contribute to its pathogenesis and disease (ds.) progression. We have previously shown that up to 6 doses of CXCR4 enriched T regulatory cells, CK0804 Tregs, can be administered safely at a fixed dose of 100 million cells, every 28 days in myelofibrosis patients (pts) with measurable disease including palpable splenomegaly, symptom burden and/ or grade 2 cytopenia despite being on ruxolitinib for at least 12 weeks. Early efficacy signal shows at least 50% decrease in symptom burden in 75% (n=9) and spleen volume reduction 25% (SVR25) in 33% (n=6). Here we present data on dose intensive expansion cohort and one year follow-up of the safety run-in cohort. Methods: Expansion cohort included a dose intensive regimen of 4 weekly infusions of CK0804 Tregs followed by 5 monthly infusions of CK0804 Tregs. Primary and secondary objective includes safety and overall response per IWG-MRT criteria at 24 weeks, respectively. All pts started on 5 mg twice daily dose or higher of ruxolitinib that was stable for at least 8 weeks. Results: In the expansion cohort, 4 pts with median age of 69.5 yrs (range, 66-78 yrs), duration of ds. of 11.5 yrs (range, 1-20 yrs), ruxolitinib duration of 4 yrs (range, 1-10 yrs) were treated. A total of 28 infusions were tolerated without any grade 3-4 treatment related adverse events in the outpatient setting without a need for hospitalization. In 3 evaluable pts, SVR25 was seen in 1 pt, and decrease in symptom burden was noticed in all 3 pts. Among the 8 evaluable pts from the initial safety run-in cohort, there were 5 responders (62.5%) (defined by decrease in at least 2 ds. measures) and 3 non-responders (37.5%). At 12 months follow-up after their first dose of CK0804, responders saw a 49% (range, 37-65%) average decrease in their symptom burden from baseline compared to an average increase of 169% (range, 110-225%) in non-responders. Continued decrease in their symptom burden, including in the subset of Fatigue (75% decrease) and Early Satiety (50% decrease), two major symptoms of the disease, was reported in responders at 6 months after the last CK0804 Treg infusion. Platelets and hemoglobin levels remained stable throughout the study and follow-up, without any dose adjustments of ruxolitinib. At baseline, the median levels of TGF- β1 (14538 ng/ml), β2 (863 ng/ml) and β3 (31 ng/ml) were found to be elevated in responders that decreased to 50% by end of treatment. Similar decrease was not observed in non-responders. Pro-fibrotic and pro-inflammatory disease relevant cytokines including FGF, sCD40L, PDGF AA and PDGF AB/BB were also decreased by 50% in responders compared to no change in non-responders. Other disease specific cytokines such as IL-8, IL-β and VEGF were reduced in majority of treated patients, while IL-6, TNFa and IL-12p70 were reduced only in responders. The anti-inflammatory IL-10, secreted by Treg cells, increased significantly in most patients. Conclusion: This more in-depth analysis of the safety run-in phase of evaluating CXCR4 enriched T regs cell therapy as addition to ruxolitinib in MF patients with sub-optimal response shows that the immune system of responders changed markedly in ways that were different than and complementary to JAK inhibition, with safety and no myelosuppressive adverse events. Extension cohort is currently enrolling with a promising early data to be presented at the meeting.
Masárová et al. (Mon,) studied this question.