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Editorials
disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian Acute Myeloid Leukemia Study Group. J Clin Oncol. 2011;29(19):2709-2716.
20. Terwijn M, van Putten WL, Kelder A, et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol. 2013;31(31):3889-3897.
Therapy-related acute lymphoblastic leukemia
Josep-Maria Ribera
21. Freeman SD, Virgo P, Couzens S, et al. Prognostic relevance of treat- ment response measured by flow cytometric residual disease detection in older patients with acute myeloid leukemia. J Clin Oncol. 2013; 31(32):4123-4131.
22. Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018;378(13):1189-1199.
Clinical Hematology Department. ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Universitat Autònoma de Barcelona, Spain
E-mail: jribera@iconcologia.net doi:10.3324/haematol.2018.200311
Therapy-related acute lymphoblastic leukemia (t- ALL) refers to ALL developed in patients who have received prior cytotoxic therapies, including chemotherapy and/or radiotherapy for solid or hemato- logic cancers. In this issue of Haematologica, Aldoss et al.1 report the largest retrospective study of patients from a single institution with analysis focused only on cases with prior exposure to cytotoxic therapies. The frequen- cy of t-ALL was 10%, an important subset of patients showed cytogenetic abnormalities similar to those found in therapy-related acute myeloid leukemias (t-AML) or therapy-related myelodysplastic syndromes (t-MDS), and the outcome of t-ALL patients was poorer than that of the de novo ALL patients, especially for those who did not undergo allogeneic hematopoietic stem cell transplanta- tion (alloHSCT).
Similar to t-AML or t-MDS, the pathogenesis of t-ALL is attributed to the genotoxic effect of cytotoxic therapies on hematopoietic progenitor cells, but the precise mech- anisms are less understood than those of therapy-related myeloid neoplasias. An underlying constitutional predis- position shared by the malignancies and ALL cannot be ruled out, especially for cases with s-ALL. In this sense, some studies have observed a higher prevalence of malig- nant neoplasms among first-degree relatives of patients with t-ALL or s-ALL. Ten to15% of therapy-related leukemias are t-ALL,2 and it is frequently confounded with the so-called secondary ALL (s-ALL), that refers to the patients with ALL with antecedent neoplasia but without exposure to cytotoxic therapy. Both t-ALL and s- ALL are infrequent (less than 2%-10% of all ALL cases)1,3- 14 (Table 1), and are unfortunately often considered together in most case series or registry studies. The pre- cise distinction of both types of ALL is important, espe- cially for t-ALL, because prior exposure to cytotoxic ther- apies could have an impact on both treatment-related morbidity and mortality and on response to chemothera- py and the subsequent use of alloHSCT.15
Clinically, t-ALL arises in older patients than de novo ALL, and there is a female and white ethnicity preponder- ance in some series, different to what occurs in newly diagnosed ALL patients. Pediatric cases of t-ALL have also been described.14 An important question is to know
whether t-ALL is biologically different from de novo ALL. No significant differences have been reported in the white blood cell (WBC) count, the frequency of central nervous system or other extramedullary infiltration, or in the frequency of the different leukemia phenotypes (T- ALL or B-cell precursor ALL), although some studies have described a lower WBC count in t-ALL patients.1 However, important differences have been observed regarding genetic background, showing a predominance of high-risk genetic subtypes in t-ALL compared with de novo ALL. The most consistent genetic abnormality found across studies is the 11q23 (KMT2A) rearrangement, fol- lowed by monosomies of chromosomes 5, 7 and/or 17, hypodiploidy, and in some studies, by the Philadelphia (Ph) chromosome (Table 1).1,2-14,16 Except for the latter rearrangement, these genetic abnormalities are similar to those found in t-AML or in t-MDS and support the etio- logic role of prior chemotherapy in the pathogenesis of t- ALL. Alterations of tumor suppressor genes at the 11q23 chromosomal regions may also predispose the cells to both solid and hematological cancers. The 11q23 rearrangements are frequently observed in patients who have received topoisomerase II inhibitors. As occurs in de novo Ph-positive ALL, the p190 BCR-ABL subtype is pre- dominant, but the frequency of associated chromosomal abnormalities (ACA, especially monosomies), is higher in cases with Ph-positive t-ALL.16 Large molecular studies are lacking in t-ALL and, consequently, the frequency of specific subgroups such as the BCR-ABL-like is unknown.
Large epidemiological studies have shown that any pre- vious malignancy can lead to an increased incidence of s- ALL or t-ALL, which establishes this ALL as a separate entity.9,11,12 Among all cancer survivors, those with prior cancer treatment have a higher probability to develop ALL than those with no prior treatment, with this increased risk being observed at any age.11,12 Regarding the type of previous solid cancer, breast cancer constitutes the most common prior solid malignancy across the series, probably related to its high frequency, the elevated utilization of alkylator and topoisomerase II inhibitors as well as radiotherapy, and the excellent long-term survival for this disease. Lymphomas and other lymphoprolifera- tive disorders encompass the most frequent antecedent of
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