Post-transplant maintenance therapy with midostaurin was safe and reduced relapse risk in patients with FLT3-mutated acute myeloid leukemia (AML), according to findings from the phase II RADIUS trial presented at the 2019 Transplantation & Cellular Therapy (TCT) Meetings of the American Society for Blood and Marrow Transplantation (ASBMT) and the Center for International Blood & Marrow Transplant Research (CIBMTR), formerly known as the BMT Tandem Meetings. The results also demonstrated that midostaurin-treated patients who experienced greater inhibition of phosphorylated FLT3 (pFLT3) had a greater likelihood of remaining disease-free.
“Some institutional [experience] and small phase II randomized studies have suggested that post-transplant [tyrosine kinase inhibition] might actually improve and enhance the outcomes of patients,” said lead study author Richard T. Maziarz, MD, from Oregon Health & Science University, during his presentation.
In the randomized, open-label, phase II RADIUS trial, investigators evaluated whether adding the tyrosine kinase inhibitor midostaurin to standard of care (SOC) extended relapse-free survival (RFS), compared with SOC alone. SOC included anti-infective and graft-versus-host disease (GVHD) prophylaxis and treatment; midostaurin 50 mg was administered twice daily in 28-day treatment cycles.
As of a data cutoff of April 30, 2018, a total of 60 patients were randomized: 30 in the midostaurin arm and 30 in the SOC arm. One patient in each arm did not receive treatment, leaving 29 evaluable patients in each arm. All participants had undergone allogeneic hematopoietic cell transplantation (alloHCT) and started maintenance treatment within 60 days post-transplant. Patient characteristics were “relatively well matched” between both groups, Dr. Maziarz noted, although patients in the midostaurin group tended to be younger than in the SOC group (median ages: 48 years and 56 years, respectively).
Half of the RADIUS participants completed all 12 treatment cycles, with a median duration of exposure of 10.5 months (range = 0.2-11.5 months) and a median dose intensity of 93 mg/day (range = 15-100 mg/day).
During 24 months of follow-up, 13 patients in the midostaurin arm and 15 in the SOC arm discontinued treatment, mostly due to adverse events (AEs) in the midostaurin arm and to consent withdrawal in the SOC arm.
Dr. Maziarz reported that there was a higher incidence of low-grade gastrointestinal AEs in the midostaurin arm, including vomiting, nausea, and diarrhea. However, there was no significant difference between incidence of grade 3/4 AEs. The authors also noted that treatment with midostaurin was not associated with an increased risk or severity of GVHD, compared with SOC (p values not provided).
Regarding 18-month RFS (the study’s primary endpoint), Dr. Maziarz said that “both arms did better than predicted,” and there was a statistically nonsignificant reduction in the relapse risk for midostaurin-treated patients. The estimated 18-month RFS was 89 percent in the midostaurin arm and 76 percent in the SOC arm (hazard ratio [HR] = 0.46; 95% CI 0.12-1.86; p=0.27).
At 24-month follow-up, the investigators observed a continued RFS benefit with midostaurin (85% vs. 76%; HR=0.60; 95% CI 0.17-2.14; p=0.43), although this was not statistically significant.
Midostaurin also appeared to prolong overall survival, but again, these results did not reach statistical significance.
The investigators also reviewed plasma inhibitory activity among midostaurin-treated patients, finding that greater inhibition of pFLT3 (>70%) was associated with improved survival outcomes, while patients with suboptimal pFLT3 inhibition (<70%) had outcomes that matched SOC-treated patients.
The small patient population of the RADIUS trial limits the generalizability of its findings, and Dr. Maziarz said that the trial was underpowered for “determining survival and was instead looking for a signal [of benefit].” He also noted a potential internal bias, because patients were enrolled after undergoing alloHCT and met criteria of good performance status, hematopoietic recovery, and adequate organ function.
Dr. Maziarz added that, in real-world clinical practice, most patients with FLT3-mutated AML are now receiving tyrosine kinase inhibitors during induction and consolidation therapy, which also may affect the role of midostaurin as post-transplant maintenance therapy.
The authors reported relationships with Novartis, which supported the study.
Maziarz RT, Fernandez H, Patnaik MM, et al. Radius: Midostaurin (mido) plus standard of care (SOC) after allogeneic stem cell transplant (alloSCT) in patients (pts) with FLT3-internal tandem duplication (ITD)–mutated acute myeloid leukemia (AML). Abstract #13. Presented at the Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR, February 20, 2019; Houston, TX.