Allo-HSCT in patients with therapy-related AML or MDS

Therapy-related myeloid neoplasm (t-MN) is a secondary malignancy that can occur after being exposed to chemotherapy. 70% of t-MN cases appear 5–7 years after being treated with an alkylating agent, while the other 30% are diagnosed 2–3 years after treatment with topoisomerase II inhibitors (e.g., anthracyclines, etoposide).

Therapy-related acute myeloid leukemia (t-AML) and myelodysplastic syndromes (t-MDS) represent up to 20% of all new myeloid neoplasm diagnoses in the United States. These patients frequently have a worse prognosis than those with primary AML or MDS, due mainly to their older age at diagnosis, higher comorbidity scores relating to their primary disease, and chromosomal abnormalities.

Compared to de novo MDS, there are fewer patients with t-MDS classified as low-risk or very low-risk, and even though these categories have more favorable prognosis, their median overall survival (OS) is similar to the higher-risk subgroups of de novo MDS. Hence, patients with t-MN are potential candidates for an earlier allogeneic stem cell transplantation (allo-HSCT).

Marie Robin, during the 47th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), reviewed the published experience with allo-HSCT in patients with t-MN.¹

CIBMTR and EBMT studies

In 2010, the Center for International Blood and Marrow Transplant Research (CIBMTR) analyzed 868 patients diagnosed with t-MN between 1990 and 2004. They reported a 5-year OS rate of 22% and defined the following factors associated with outcomes:

• Age <35 years;
• Cytogenetics;
• Disease status at the time of transplantation; and
• Donor type.

Previously, the EBMT had also shared similar survival rates with allo-HSCT in 461 patients with t-MN and identified similar risk factors. However, when analyzing their results according to the primary disease, they found that patients with post-lymphoid disease t-MN experienced shorter relapse-free survival and higher non-relapse mortality.

The conditioning regimen intensity may also play a role in the risk of relapse and survival outcomes: in 2018, the EBMT published a retrospective study with 535 patients with t-AML and reported that patients who received a reduced-intensity conditioning regimen (vs myeloablative conditioning) showed an increase in relapse incidence (hazard ratio [HR], 1.52; 95% CI, 1.02–2.26; p = 0.04), lower leukemia-free survival (HR, 1.52; 95% CI, 1.12–2.05; p = 0.007), and lower OS (HR, 1.51; 95% CI, 1.09–2.09; p = 0.012).²

Swedish registry

A total of 282 patients with t-AML were treated with intensive chemotherapy in Sweden in 1997–2013. The analysis of this cohort demonstrated a clear advantage of allo-HSCT in terms of OS in patients with t-AML, compared to chemotherapy consolidation (HR, 0.61; 95% CI, 0.39–0.97).¹

Japanese registry

In line with the previous studies, when analyzing the outcomes of 565 patients with t-MN who underwent an allo-HSCT, their 3-year OS rate (31%) was equivalent to that in patients with secondary MN (32%) but significantly worse than de novo MN (44%, p < 0.001). Interestingly, although de novo MDS presented higher better outcomes than AML, OS in t-MDS was similar to that in t-AML (34% vs 30%, p = 0.4362).³

This study identified the following significant risk factors for poor survival: age >55 years, Eastern Cooperative Oncology Group performance status 2–4, progressive disease status at the time of transplantation, and intermediate-poor karyotype. Type of primary cancer was not found as a significant risk factor in this cohort.

Conclusion

Due to the poor prognosis of t-MN, allo-HSCT is indicated in fit patients. In fact, allo-HSCT might be the only curative treatment option for these patients today. However, most of them will not be eligible due to age, performance status, or comorbidities.

If eligible for transplant, it is crucial to assess the karyotype and the presence of any specific mutations (i.e., TP53) that could help predict the outcomes and, thus, implement specific strategies pre or post allo-HSCT. According to the limited published experience, between 30% and 50% of patients with t-MN eligible for allogeneic transplantation can be cured.¹