Features of Secondary Acute Promyelocytic Leukemia
Features of Secondary Acute Promyelocytic Leukemia
Although therapy-related myeloid leukemias most often are composed of myeloblasts or monoblasts, secondary APL is well recognized. The development of t-APL is seen in patients with solid tumors and lymphoma and is particularly associated with prior treatment with topoisomerase II inhibitors. Several studies have shown that the prognosis of t-APL is significantly better than other t-AMLs, although some studies suggest that the prognosis of t-APL is slightly less favorable than the prognosis of de novo APL. Similar findings have been reported in patients with multiple sclerosis who were treated with the topoisomerase II inhibitor mitoxantrone and APL subsequently developed. Although these studies investigated the clinical features of secondary APL, they did not include a detailed comparison of the laboratory features of de novo and secondary APL.
In this 10-year retrospective review of new admissions for APL at our institution, we examined not only clinical findings but also laboratory findings in patients with secondary APL, including the immunophenotype and morphologic features of the abnormal promyelocytes and molecular and cytogenetic findings. We found that secondary APL is not uncommon and accounted for 14% of newly diagnosed APL cases in this series. The median interval between treatment for the initial neoplasm and the development of t-APL was 2.8 years, which is in keeping with previous research that has found that many cases of t-APL arise within 3 years. Cases of secondary APL did not have laboratory values or pathologic findings that distinguished them from cases of de novo APL. None of the patients in this series with secondary APL developed recurrent disease or died of leukemia, although 2 patients died of the primary disease and 1 patient was lost to follow-up. Although this series is small, our results agree with the general notion that secondary APL does not have as unfavorable a prognosis as other forms of secondary AML.
This review of the morphologic features and immunophenotype of abnormal promyelocytes in de novo and secondary cases of APL demonstrated that there were no specific findings that were characteristic or diagnostic of secondary APL. The M3h and M3v variants of secondary APLs were morphologically indistinguishable from de novo APL. The abnormal promyelocytes in secondary APL demonstrated a range of immunophenotypes similar to those seen in de novo APL. Of note, the expression of CD56 on the abnormal promyelocytes in APL has been shown to be an independent adverse prognostic factor for relapse. In this series, CD56 was expressed on abnormal promyelocytes in 11% of de novo APL cases (6/55) and 17% of secondary APL cases (1/6). Despite the association between CD56 expression and poor prognosis, none of the patients with CD56+ abnormal promyelocytes died of disease or had disease that later recurred.
The secondary APLs also did not show any characteristic cytogenetic findings compared with de novo APL. The finding that t-APLs do not have higher rates of additional chromosomal abnormalities agrees with previous research that showed similar rates of additional karyotypic abnormalities in de novo and t-APL. In addition, none of the karyotypic abnormalities seen in the cases of secondary APL were one of the mutations typically associated with t-AML such as complete or partial loss of chromosome 5 or 7. The frequent identification of FLT3 mutations in t-APL was expected, as many cases of APL exhibit mutations in this tyrosine kinase. In addition, the cases of M3v had more frequent FLT3 mutations than did cases of classic APL, which has been previously decribed. While FLT3 mutations are considered a poor prognostic indicator in most AMLs, in APL, the presence of an FLT3 mutation seems to suggest a somewhat poorer prognosis, but not to the same degree as in other forms of AML. In the small sample in this study, FLT3 mutations did not adversely affect the prognosis of secondary APL.
In 2 cases in this series, secondary APL developed in the setting of chronic immunosuppression. Both involved patients were treated with the cytotoxic antimetabolite mycophenolate and, thus, met the criteria for a treatment-related myeloid neoplasm. Mycophenolate was implicated in the development of therapy-related hematologic neoplasms in the 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, and a recent case report described the development of secondary APL following renal transplantation in a patient treated with mycophenolate and other immunosuppressants. We did not identify any characteristic clinical or pathologic features in the 2 cases of secondary APL that arose in chronically immunosuppressed patients treated with mycophenolate.
This cohort of patients with secondary APL was no more likely to experience disease recurrence or die of leukemia than patients with de novo APL. Furthermore, we did not identify any morphologic, laboratory, or pathologic findings that were characteristic of secondary APL, and the range of phenotypes and genetic anomalies was similar to those seen in de novo APL. While this data set is limited, our findings suggest that secondary APL may not be biologically distinct from de novo APL and may not have an adverse prognosis and, therefore, should be considered as distinct from other treatment-related myeloid neoplasms. Further study of this or other specific subgroups of therapy-related myeloid disorders may increase our understanding of the heterogeneity of these diseases and lead to their further subclassification.
Discussion
Although therapy-related myeloid leukemias most often are composed of myeloblasts or monoblasts, secondary APL is well recognized. The development of t-APL is seen in patients with solid tumors and lymphoma and is particularly associated with prior treatment with topoisomerase II inhibitors. Several studies have shown that the prognosis of t-APL is significantly better than other t-AMLs, although some studies suggest that the prognosis of t-APL is slightly less favorable than the prognosis of de novo APL. Similar findings have been reported in patients with multiple sclerosis who were treated with the topoisomerase II inhibitor mitoxantrone and APL subsequently developed. Although these studies investigated the clinical features of secondary APL, they did not include a detailed comparison of the laboratory features of de novo and secondary APL.
In this 10-year retrospective review of new admissions for APL at our institution, we examined not only clinical findings but also laboratory findings in patients with secondary APL, including the immunophenotype and morphologic features of the abnormal promyelocytes and molecular and cytogenetic findings. We found that secondary APL is not uncommon and accounted for 14% of newly diagnosed APL cases in this series. The median interval between treatment for the initial neoplasm and the development of t-APL was 2.8 years, which is in keeping with previous research that has found that many cases of t-APL arise within 3 years. Cases of secondary APL did not have laboratory values or pathologic findings that distinguished them from cases of de novo APL. None of the patients in this series with secondary APL developed recurrent disease or died of leukemia, although 2 patients died of the primary disease and 1 patient was lost to follow-up. Although this series is small, our results agree with the general notion that secondary APL does not have as unfavorable a prognosis as other forms of secondary AML.
This review of the morphologic features and immunophenotype of abnormal promyelocytes in de novo and secondary cases of APL demonstrated that there were no specific findings that were characteristic or diagnostic of secondary APL. The M3h and M3v variants of secondary APLs were morphologically indistinguishable from de novo APL. The abnormal promyelocytes in secondary APL demonstrated a range of immunophenotypes similar to those seen in de novo APL. Of note, the expression of CD56 on the abnormal promyelocytes in APL has been shown to be an independent adverse prognostic factor for relapse. In this series, CD56 was expressed on abnormal promyelocytes in 11% of de novo APL cases (6/55) and 17% of secondary APL cases (1/6). Despite the association between CD56 expression and poor prognosis, none of the patients with CD56+ abnormal promyelocytes died of disease or had disease that later recurred.
The secondary APLs also did not show any characteristic cytogenetic findings compared with de novo APL. The finding that t-APLs do not have higher rates of additional chromosomal abnormalities agrees with previous research that showed similar rates of additional karyotypic abnormalities in de novo and t-APL. In addition, none of the karyotypic abnormalities seen in the cases of secondary APL were one of the mutations typically associated with t-AML such as complete or partial loss of chromosome 5 or 7. The frequent identification of FLT3 mutations in t-APL was expected, as many cases of APL exhibit mutations in this tyrosine kinase. In addition, the cases of M3v had more frequent FLT3 mutations than did cases of classic APL, which has been previously decribed. While FLT3 mutations are considered a poor prognostic indicator in most AMLs, in APL, the presence of an FLT3 mutation seems to suggest a somewhat poorer prognosis, but not to the same degree as in other forms of AML. In the small sample in this study, FLT3 mutations did not adversely affect the prognosis of secondary APL.
In 2 cases in this series, secondary APL developed in the setting of chronic immunosuppression. Both involved patients were treated with the cytotoxic antimetabolite mycophenolate and, thus, met the criteria for a treatment-related myeloid neoplasm. Mycophenolate was implicated in the development of therapy-related hematologic neoplasms in the 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, and a recent case report described the development of secondary APL following renal transplantation in a patient treated with mycophenolate and other immunosuppressants. We did not identify any characteristic clinical or pathologic features in the 2 cases of secondary APL that arose in chronically immunosuppressed patients treated with mycophenolate.
This cohort of patients with secondary APL was no more likely to experience disease recurrence or die of leukemia than patients with de novo APL. Furthermore, we did not identify any morphologic, laboratory, or pathologic findings that were characteristic of secondary APL, and the range of phenotypes and genetic anomalies was similar to those seen in de novo APL. While this data set is limited, our findings suggest that secondary APL may not be biologically distinct from de novo APL and may not have an adverse prognosis and, therefore, should be considered as distinct from other treatment-related myeloid neoplasms. Further study of this or other specific subgroups of therapy-related myeloid disorders may increase our understanding of the heterogeneity of these diseases and lead to their further subclassification.
