Pacritinib, Sirolimus, and Tacrolimus Combo Fails to Improve GVHD Outcomes
A phase 2 study found that a combination of pacritinib, sirolimus, and tacrolimus successfully suppressed pSTAT3 and Th1/Th17 cells, but failed to prevent acute graft-versus-host disease following allogeneic transplant.
Microscopic image of bone marrow cells - Generated with Google Gemini AI
A prophylactic regimen of pacritinib (Vonjo), sirolimus (Rapamune), and tacrolimus (Prograf) suppressed pSTAT3 and Th1/Th17 cells, but did not effectively prevent acute graft-vs-host disease (GVHD) following allogeneic hematopoietic cell transplant (alloHCT), according to findings from a phase 2 study (NCT02891603).1
“Despite a presumably favorable increased ratio of [regulatory T cells] to Th1/Th17 cells, [pacritinib, sirolimus, and tacrolimus] did not improve GVHD prevention after matched related or unrelated alloHCT. We found no clinical, immunologic, or medication adherence factor that correlated with acute GVHD breakthrough on [pacritinb, sirolimus, and tacrolimus],” authors wrote in the study published in Blood.
The primary end point of the study was suppression of pSTAT3, CD4, and T cells at day +21, and the secondary end point was the reduction of cumulative incidence of grade 2 to 4 acute GVHD by day +100. The study did meet its primary end point and reduced the percentage of pSTAT3, CD4, and T cells to 9.62% at day +21. However, the incidence of grade 2 to 4 acute GVHD by day +100 was 46% with pacritinib, sirolimus, and everolimus vs a historic value of 43% with sirolimus and tacrolimus alone.
The phase 1 portion of the study showed that pacritinib, the JAK2 inhibitor, at a dose of 100 mg orally twice daily from day 0 to +70 plus sirolimus and tacrolimus was safe and did not lead to pan-JAK myelosuppression following alloHCT.
In the phase 2 portion, patients with acute leukemia, myelodysplastic syndrome, chronic myeloid leukemia, myeloproliferative neoplasms, and Hodgkin or non-Hodgkin lymphoma were eligible for enrollment. These patients could have a matched-related or -unrelated donor for alloHCT.
The overall survival was 71% (95% CI, 51%-85%), and 11% (95% CI, 2.6%-25%) of patients experienced relapse by 12 months. Non-relapse mortality by 12 months was 29% (95% CI, 13%-46%).
Of 13 patients who experienced grade 2 to 4 acute GVHD, 11 were treated with steroid therapy, and 6 had steroid-refractory disease that required a next line of treatment. Five of these patients died from GVHD-associated complications.
Studies are continuing to evaluate pacritinib as a therapy for chronic GVHD, including 1 sponsored by the National Cancer Institute.2 This phase 1/2 study (NCT05531786) is investigating 100mg or 200mg doses ofpacritnib in patients with moderate to severe chronic GVHD following alloHCT that is refractory to previous therapies. The study’s primary end points are safety and overall response rate, and secondary end points include pharmacokinetics, safety, and clinical outcomes.
REFERENCES:
1. Pidala JA, Shernan HG, Walton K, et al. JAK2/mTOR inhibition fails to prevent acute GVHD despite reduced Th1/Th17 cells: final phase II trial results. Blood. 2023;142(Suppl 1):722.doi:10.1182/blood.2024024789
2. Phase I/II study of pacritinib, A JAK2/IRAK1/CSF1R inhibitor, in refractory chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). ClinicalTrials.gov. Updated August 1, 2024. Accessed August 8, 2024. https://clinicaltrials.gov/study/NCT05531786
Iomab-B Leads to More Durable Responses vs alloHCT in AML Treatment
September 24th 2024Findings from the phase 3 SIERRA study showed that Iomab-B was associated with a higher durable complete response rate vs allogeneic cell transplant in older patients with relapsed/refractory acute myeloid leukemia.
Read More
