Survival of TP53-mutated acute myeloid leukemia patients receiving allogeneic stem cell transplantation after first induction or salvage therapy: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND)

We conducted a multi-center study to analyze factors predicting survival among patients with TP53-mutated (m) AML receiving allogeneic hematopoietic stem cell transplant (allo-HSCT) in the recent era. Out of 370 TP53m AML patients, 68 (18%) patients were bridged to allo-HSCT. The median age of the patients was 63 years (range, 33–75), 82% of patients had complex cytogenetics and 66% of patients had multi-hit TP53m. Forty three percent received myeloablative conditioning and 57% received reduced intensity conditioning. The incidence of acute graft versus host disease (GVHD) was 37% and chronic GVHD was 44%. The median event-free survival (EFS) from the time of allo-HSCT was 12.4 months (95% CI: 6.24–18.55) and median overall survival (OS) was 24.5 months (95% CI: 21.80–27.25). In multivariate analysis utilizing variables that showed significance in univariate analysis, complete remission at day 100 post allo-HSCT retained significance for EFS (HR: 0.24, 95% CI: 0.10–0.57, p = 0.001) and OS (HR: 0.22, 95% CI: 0.10–0.50, p ≤ 0.001). Similarly, occurrence of chronic GVHD retained significance for EFS (HR: 0.21, 95% CI: 0.09–0.46, p ≤ 0.001) and OS (HR: 0.34, 95% CI: 0.15–0.75, p = 0.007). Our report suggests that allo-HSCT offers the best opportunity to improve long-term outcome among patients with TP53m AML.


INTRODUCTION
TP53 mutated (m) acute myeloid leukemia (AML) is associated with high relapse rate and poor overall survival (OS) [1][2][3]. Response to cytotoxic chemotherapy is highly dependent on the presence of intact p53 to enable the induction of apoptosis. As a result, TP53m myeloid neoplasms respond poorly to cytotoxic chemotherapy [4][5][6]. While allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potential curative option for high-risk AML, earlier reports demonstrated a lack of benefit of allo-HSCT in patients with TP53m AML [7][8][9][10][11]. Lack of survival benefit with allo-HSCT was associated with high treatment failure rates and persistence of TP53m clones after transplant [11,12]. However, allo-HSCT in first remission (CR1) was found to reduce the risk of relapse and mortality significantly [12].
Over the last 5-7 years, the advent of several novel molecular targeted therapies has provided an opportunity for an individualized, risk-adapted approach for the management of AML [13][14][15][16][17]. However, there has been limited success in improving remission rates of patient with TP53m AML [4,[18][19][20][21][22]. Pollyea et al. [23] evaluated efficacy of venetoclax plus azacitidine vs azacitdine alone in treatment-naïve AML patients harboring poor-risk cytogenetics (CG) with or without TP53m, using data from VIALE-A trial as well as data from phase Ib study of venetoclax plus azacitidine or decitabine. In patients with poor risk CG and TP53m, venetoclax plus azacitidine vs. azacitidine alone resulted in composite CR rate of 41% vs. 17%, however median duration of response in months (6.5 vs. 6.7) and median OS (5.2 vs. 4.9) was not different, respectively. The proportion of patients with TP53m AML and had allo-HSCT was not reported in this analysis.
We recently conducted a multi-center study analyzing the outcome of TP53m AML patients with evolving frontline therapies over the last one decade [24]. Despite the increased use of venetoclax-based therapy in the past decade, the only factor that seemed to improve survival was allo-HSCT. In this report, we specifically evaluated the outcome of patients with TP53m AML undergoing allo-HSCT after induction or salvage chemotherapy.

PATIENTS AND METHODS
We conducted a multi-center, retrospective study through the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND) involving acute leukemia experts from 10 academic centers, with a goal to characterize the outcome of patients with acute leukemia in the realworld setting. For this study, after institutional review board approval, the databases of the participating institutions were screened for eligible adult (≥18 years old) patients with a diagnosis of TP53m AML, treated between November 2012 and December 2021. We analyzed factors predicting longterm survival among TP53m AML patients receiving allo-HSCT.
Response to treatment was defined according to 2017 European Leukemia Net (ELN) consensus guidelines [25]. The overall response rate (ORR) was defined by achieving a complete remission (CR) with or without count recovery (CRi), partial remission (PR) or morphologic leukemia free state (MLFS). Measurable residual disease (MRD) assessment was done by flow cytometry using bone marrow aspirate at a sensitivity threshold of ≤1 ×10 −4 (0.01%) per standard practices at participating centers. Following library preparation by hybrid capture, next generation sequencing (NGS) was performed using extracted DNA from bone marrow aspirate specimens with post-sequencing analysis of tumor-associated mutations. NGS testing was developed, and its performance characteristics determined by the participating institutions in compliance with CLIA requirements. Acute and chronic graft versus host disease (GVHD) were defined according to the established criteria [26,27].

Statistical analysis
Continuous variables were summarized as median (range) while categorical variables were reported as frequency (percentage). The Kaplan-Meier method was used to estimate event free survival (EFS), defined as time from transplant to relapse or death. The median overall survival (OS) was calculated from time of diagnosis to death or last follow-up. Logistic regression models were used to determine the univariate and multivariate predictors of complete response to induction. Cox proportional hazards regression models were used to determine the univariate and multivariate predictors of overall mortality and progression. Multivariable models included all significant univariate predictors. All tests were two-sided with a p value < 0.05 considered statistically significant.

DISCUSSION
Our report suggests that allo-HSCT is associated with improved long-term outcomes among patients with TP53m AML after first induction or salvage therapy. In multivariate analysis, significant improvement in survival was observed among patients who were in complete remission at day 100 post allo-HSCT or had chronic GVHD.
Compared to non-TP53m AML, TP53m AML has lower response rates to intensive induction chemotherapy, HMA or venetoclaxbased therapies with median OS in the range of 5-10 months. Though allo-HSCT is considered a potential curative option for high-risk AML, multiple studies in the past have reported poor outcomes in TP53m AML patients undergoing allo-HSCT, with relapse rates as high as 80-90% [7,8,10,11,28]. Dismal outcomes with allo-HSCT have been attributed to the inability to achieve deeper response prior to transplant, the persistence of TP53m clone and the co-occurrence of complex CG [12,29]. On the other hand, other studies have shown that outcomes can be improved if allo-HSCT is pursued in CR1 [12,30]. In the referenced study by Short et al., 20/202 (10%) patients underwent allo-HSCT; the patients who received allo-HSCT in CR1 had a median OS of 17.6 months compared to 9.1 months in patients who had allo-HSCT after further therapies. In our earlier report evaluating outcomes of TP53m AML with evolving frontline therapies from a multi-center cohort, there was no significant difference in survival with newer therapies, including venetoclax-based treatment and CPX-351. TP53m AML with complex CG were associated with inferior EFS and OS, whereas allo-HSCT retained significance for better EFS and OS in multivariate analysis [24]. In this study, we specifically analyzed characteristics of patients who underwent allo-HSCT and predictors for survival outcomes after transplant. Day 100 (post allo-HSCT) CR/CRi (33/69 [48%] MRD negative) was predictive of better EFS and OS. These findings are in line with previous observations that early relapse is prognostic for longterm outcome in patients with high-risk AML [31,32]. Unlike previously published data, we observed relative benefit of allo-HSCT in improving long-term outcomes even after more than one line of therapy in eligible patients.
In univariate/multivariate analysis, survival was not significantly influenced by attaining pre-transplant MRD-negative CR by flow cytometry or transplantation with persistent disease. A recently reported randomized phase III study evaluated the role of intensive remission induction chemotherapy prior to allo-HSCT. The study compared immediate allo-HSCT after sequential conditioning without attempt to induce a CR vs. attempting to induce remission with intensive chemotherapy prior to allo-HSCT in patients with high risk AML [33]. The study concluded that patient with sub-optimal (less than CR) response after first induction therapy or relapsed AML do not benefit from salvage   intensive chemotherapy to attain CR prior to allo-HSCT. Watchful waiting and sequential conditioning prior to allo-HSCT results in comparable OS and may be a preferred option once stem cell donor is available. This may be a strategy to consider in TP53m AML which are inherently resistant to cytotoxic therapy and antileukemia activity through donor allo-immune response can be aimed to improve long-term outcome. Clearance of TP53m by NGS testing prior to allo-HSCT has been shown to have a favorable impact on survival [34]. Although we saw a trend for better EFS among patients with undetectable TP53m by NGS prior to allo-HSCT, it was not statistically significant. We acknowledge that our observation was limited by a small proportion of patients with serial mutational data going into allo-HSCT. The utility of azacitidine maintenance therapy post allo-HSCT in patients with high-risk MDS/AML has failed to show a survival benefit in patients with high-risk MDS/AML [35]. Only 12 (18%) patients in our cohort received HMA maintenance therapy post allo-HSCT, and we did not observe a benefit of maintenance therapy in improving EFS or OS. Venetoclax and eprenetapopt maintenance therapies post allo-HSCT are being actively explored, and initial results are encouraging [36][37][38]; these agents may be helpful in further improving long-term outcomes in TP53m AML after allo-HSCT.
The intensity of the conditioning regimen prior to allo-HSCT is known to impact clinical outcome, where MAC compared to RIC is associated with improved relapse-free survival but higher treatment-related mortality [39]. Lindsley et al. reported the prognostic impact of myeloid mutations on outcome of allo-HSCT recipient using the CIBMTR database [7]. In this analysis, TP53m was present in 19% of patients with MDS/AML and was associated with shorter survival compared to TP53 wild type. The adverse prognostic impact of TP53m was similar in patients receiving MAC vs RIC regimen. Similarly, we did not observe a significant association between conditioning intensity and outcomes in our TP53m AML cohort.
The anti-leukemic activity of allo-HSCT does not solely rely on conditioning intensity but also on the immune-mediated graftversus-leukemia (GVL) effect [40]. The donor alloimmune responses can also be directed against healthy tissues, which is known as GVHD. GVHD and GVL frequently co-occur in patients with leukemia undergoing allo-HSCT. The occurrence of chronic GVHD is reported to be associated with lower relapse risk and better OS [40,41]. In our analysis, 30 (44%) patients had chronic GVHD (n = 11 with moderate to severe). The occurrence of chronic GVHD correlated with improved EFS and OS. These data suggest that an alloimmune response is predictive of improved survival post-transplant even in patients with high-risk, specifically TP53m AML.
While acknowledging the limitations of the retrospective design of our study and the inherent inter-institutional heterogeneity, this data represents outcomes from a large multi-center cohort of patients with TP53m AML analyzed by NGS and followed longitudinally after allo-HSCT. In conclusion, our study suggests that allo-HSCT still offers the best chance to improve long-term outcomes in patients with TP53m AML. Patients should be selected appropriately, receive effective induction strategies to achieve remission without significant toxicities and undergo close monitoring after allo-HSCT.