1.
Persistent IDH mutations are not associated with increased relapse or death in patients with IDH-mutated acute myeloid leukemia undergoing allogeneic hematopoietic cell transplant with post-transplant cyclophosphamide
Ravindra, N., Dillon, L. W., Gui, G., Smith, M., Gondek, L. P., Jones, R. J., Corner, A., Hourigan, C. S., Ambinder, A. J.
Bone marrow transplantation. 2024
2.
Cell-free DNA measurable residual disease as a predictor of postallogeneic hematopoietic cell transplant outcomes
Pasca, S., Guo, M. Z., Wang, S., Stokvis, K., Shedeck, A., Pallavajjala, A., Shams, C., Pallavajjala, R., DeZern, A., Varadhan, R., et al
Blood advances. 2023
Abstract
The measurable residual disease (MRD) assessment provides an attractive predictor of alloHCT outcomes. Cell-free DNA (cfDNA) has been applied to diagnosis, early detection, and disease burden monitoring in various tumors but its utility as an MRD test in myeloid malignancies has not been systematically evaluated. We sought to determine the differential sensitivity between bone marrow (BM) and cfDNA MRD and to assess the effect of cfDNA MRD on alloHCT outcomes. The technical and clinical validation cohort including 82 patients participating in clinical trials (BMT CTN-0201 and 0402) were utilized. Ultra-deep error-corrected targeted sequencing was performed on plasma and bone marrow-derived DNA. We demonstrated that 94.6% (range 93.9-95.3%) of cfDNA was derived from hematopoietic tissue. The mutant allele fraction was congruent between BM and cfDNA (rho = 0.8, p<0.0001), however, cfDNA appeared to be more sensitive in detecting clones with variant allele frequency (VAF) <0.26%. CfDNA-MRD clearance by day 90 post-alloHCT (D90) was associated with improved relapse-free survival (RFS, median survival not reached vs 5.5 months, p <0.0001) and overall survival (OS, median survival not reached vs 7.3 months, p < 0.0001) when compared to patients with persistent MRD. Irrespective of pre-alloHCT MRD, D90 cfDNA MRD was associated with inferior 2-year OS (16.7% vs. 84.8%, p <0.0001) and RFS (16.7% vs. 80.7%, p <0.0001). CfDNA appears to be an accurate, minimally invasive alternative to BM aspirates in MRD assessment and confers important prognostic implications in patients with myeloid malignancies undergoing alloHCT.
3.
A prospective study of peri-transplant sorafenib for FLT3-ITD AML patients undergoing allogeneic transplantation
Pratz, K. W., Rudek, M. A., Smith, B. D., Karp, J., Gojo, I., Dezern, A., Jones, R. J., Greer, J., Gocke, C., Baer, M. R., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
FLT3-ITD mutated acute myeloid leukemia (AML) remains a therapeutic challenge. FLT3 inhibition in the setting of minimal residual disease and a new immune system via allogeneic transplantation offers a promise of improved survival for these patients. We performed a prospective study of patients with FLT3-ITD AML undergoing allogeneic transplant was conducted to evaluate the safety, tolerability, and outcome of sorafenib administered peri-transplant. Sorafenib dosing was individualized, starting at 200 mg BID, and titrated based on tolerability or toxicities until a tolerable dose was identified. Forty-four patients, with a median age of 52, undergoing allogeneic transplant were started on sorafenib in the peri-transplant period (21 pre-transplant). The median duration of post-transplant follow up is 27.6 months (range, 5.2-60.4). Overall survival was 76% at both 24 and 36 months. Event-free survival at 24 and 36 months was 74% and 64%, respectively. Ten patients died in the post-transplant period, with six deaths due to relapsed leukemia and four from transplant-associated toxicity. Tolerable doses ranged from 200 mg QOD to 400 mg BID with similar exposure. Correlative studies evaluating FLT3 inhibition via a plasma inhibitory activity assay showed consistent inhibition of FLT3 at all tolerability-determined dosing levels. Sorafenib is well tolerated in the peri-transplant setting irrespective of the conditioning intensity or the donor source. Our findings indicate that sorafenib dosing can be individualized in the post-transplantation setting according to patient tolerability. This approach results in effective in vivo FLT3 inhibition and yields encouraging survival results.