Patients with myelodysplastic syndrome harboring a TP53 mutation experienced a survival benefit with allogeneic hematopoietic cell transplantation compared with non-HCT treatment regardless of TP53 allelic status.
Patients with myelodysplastic syndrome (MDS) harboring a TP53 mutation experienced a survival benefit with allogeneic hematopoietic cell transplantation (HCT) compared with non-HCT treatment regardless of TP53 allelic status, according to findings from an analysis of the phase 2 Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1102 study (NCT02016781) published in the Journal of Clinical Oncology.1
Findings from a univariate analysis showed that, irrespective of treatment strategy, patients with a TP53 mutation (n = 87) experienced a 3-year overall survival (OS) rate of 21% (standard error [SE] ± 5%) compared with 52% (SE ± 4%) among patients who were TP53 wild-type (n = 222; HR, 2.55; 95% CI, 1.86-3.50; P < .001). Additionally, the 3-year OS rate among patients with a single TP53 mutation (n = 39) was comparable with that of patients with a TP53 multi-hit mutation (n = 48), at 22% (SE ± 8%) vs 20% (SE ± 6%), respectively (HR, 1.29; 95% CI, 0.79-2.11; P = .31).
When HCT was used as a time-dependent covariate, patients with a TP53 mutation who received HCT (n = 48) experienced a 3-year OS rate of 23% (SE ± 7%) vs 11% (SE ± 7%) in patients who were treated with non-HCT therapy (n = 32; HR, 1.76; 95% CI, 1.02-3.06; P = .04). Moreover, the 3-year OS rate among patients with very high-risk MDS per the Molecular International Prognostic Scoring System per molecular International Prostate Symptom Score (IPSS-M) without a TP53 mutation who received HCT (n = 22) was significantly improved compared with those with the same risk profile and mutational status who received non-HCT therapy (n = 8), at 68% (SE ± 10%) vs 0% (SE ± 12%), respectively (P = .001).
“The absence of a non-HCT control group in [other] retrospective analyses has called into question whether the long-term survival observed in these studies was reasonably attributable to the transplantation intervention,” investigators wrote. “In this study, we directly addressed this question and now conclude definitively that reduced intensity transplantation mediates long-term survival for patients with TP53-mutated MDS compared with non-HCT treatment. Moreover, we show that the benefit of HCT over non-HCT treatment was independent of TP53 allelic state and not restricted to specific subgroups of TP53-mutated MDS.”
Previously published findings from the primary analysis of BMT CTN 1102 showed that patients who received reduced intensity conditioning HCT (n = 260) achieved a 3-year OS rate of 47.9% (95% CI, 41.3%-54.1%) compared with 26.6% (95% CI, 18.4%-35.6%) among those who were treated with non-HCT therapy or best supportive care (n = 124), for an absolute difference of 21.3% (95% CI, 10.2%-31.8%; P = .0001). The 3-year leukemia-free survival rates were 35.8% (95% CI, 29.8%-41.8%) vs 20.6% (95% CI, 13.3%-29.1%), respectively (absolute difference, 15.2%; 95% CI, 13.3%-29.1%; P = .003).2
BMT CTN 1102 was a multicenter prospective trial that evaluated the efficacy of reduced intensity conditioning HCT (donor arm) vs that of hypomethylating therapy or best supportive care (no donor arm) in patients with IPSS intermediate-2 or high-risk de novo MDS who were 50 to 75 years old. To perform their genetic analysis of BMT CTN 1102, study authors performed targeted DNA sequencing on frozen whole blood samples collected at the time of enrollment, which were available for 229 patients in the donor arm and 80 patients in the no donor arm. Baseline patient characteristics did not differ significantly between those in the donor and no donor arms.1
Patients included in the genetic analysis (n = 309) had a median age of 66.9 years (range, 50.1-75.3), with most patients being over 65 years old (61.8%). Most patients were female (62.1%), had IPSS intermediate-2 disease (66.7%), and complex karyotype (65.0%). At baseline, the median hemoglobin was 9.3 g/dL (range, 8.1-10.7) and the median platelet count was 70 x 109/L (range, 34-132).
In addition to a univariate analysis, investigators constructed 2 multivariable models adjusted for age at enrollment, performance status, IPSS risk status, MDS disease duration, and clinical and genetic variables. One model was based on random assignment on the basis of donor availability and the other compared HCT vs non-HCT treatment with HCT representing a time-dependent covariate.
Additional findings from the univariate analysis showed that, outside of TP53 mutations, the presence of KMT2Apartial tandem duplications was associated with a decrease in 3-year OS rate compared with those who did not have these duplications (HR, 2.21; 95% CI, 1.22-3.99; P = .009). However, patients with a germline DDX41 mutation (HR, 0.39; 95% CI, 0.17-0.87; P = .022) and somatic mutations in STAG2 (HR, 0.57; 95% CI, 0.34-0.96; P = .034) displayed superior OS compared with those who did not have these mutations.
Results from the donor vs no donor analysis revealed that patients in the donor arm experienced an OS improvement compared with those assigned to the no donor arm (HR, 1.60; 95% CI, 1.10-2.32; P = .013). Among patients with a TP53 mutation, assignment to the donor arm did not significantly improve OS compared with the no donor arm (HR, 1.76; 95% CI, 0.95-3.26; P = .073).
In the model that compared HCT with non-HCT treatment, patients who received HCT (n = 197) experienced a significantly lower risk of death compared with those treated with non-HCT therapies (n = 78; HR, 2.31; 95% CI, 1.53-3.49; P < .001). Findings from this model showed that patients with a TP53 mutation had a much greater risk of dying if they did not receive HCT vs those who did (HR, 3.89; 95% CI, 1.87-8.12; P < .001), which study authors noted could signify that, “…HCT might improve long-term survival in patients with mutated TP53, independent of other risk factors.” Investigators also found molecular clearance of TP53 mutation before HCT not to be predictive of long-term survival.
“Together, these data indicate that no patient with TP53-mutated MDS should be excluded from consideration for HCT a priori on the basis of TP53 status alone. Despite the relative benefit of HCT over non-HCT treatment, however, the absolute survival benefit remains modest, meriting value-based discussions between physicians and patients on the appropriateness of transplantation,” study authors concluded.