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Editorials
The -7 chromosomal abnormalities with signs of myelodysplasia in chronic myeloid leukemia as a major red signal
Emilie Cayssials and François Guilhot
Inserm CIC 1402, University Hospital of Poitiers, CHU de Poitiers, France E-mail: GUILHOT FRANÇOIS - fr.guilhot@wanadoo.fr
doi:10.3324/haematol.2019.217034
Chronic myeloid leukemia (CML) is a leukemic dis- order the prognosis of which has been revolution- ized by the use of several generations of tyrosine kinase inhibitors (TKI). During the course of treatment, patients can develop chromosomal abnormalities in addi- tion to Philadelphia-positivity (Ph+).1 These Ph+ clonal chro- mosomal abnormalities (CCA/Ph+) could be considered markers of disease progression. A subgroup of patients has been clearly identified with fewer responses and worse outcome.2 In addition, a few patients can also develop clonal chromosomal abnormalities in Ph-negative (Ph-) cells (CCA/Ph-). Based on small case series and anecdotal reports, the European Leukemia Net (ELN)3 and the National Comprehensive Cancer Network Guidelines4 did not consider that the presence of CCA/Ph- negatively affects the prognosis provided there was no sign of bone marrow (BM) dysplasia, but chromosome -7/del(7q) abnormalities were identified as a red signal. Since 2001, a number of cases with chromosome 7 abnormalities have been reported, some of them harboring signs of myelodysplastic syndrome (MDS) or of acute myeloid leukemia (AML).5-7 The precise risk of MDS or AML with 7/del(7q) abnormalities is unclear and most of the cases have been reported with a short follow up.
In this issue of Haematologica, Bidet et al.8 report on the largest group of 26 CML patients presenting -7/del(7q) abnormalities treated front line with TKI with a median follow up of 6.47 years. These patients achieve lower cumulative incidence of deep molecular response, more frequently present BM signs of dysplasia, and are more frequently switched to second-generation TKI.
It is important to point out that CCA/Ph- clones can only be identified when patients with CML achieve a cytogenetic response. Thus, if physicians want to capture these clones, they should propose that patient undergoes BM cytogenetic analysis during the course of the disease, and at least for the first two years. In addition, BM smears are also essential to detect signs of MDS/AML. Clonal additional abnormalities are usually identified as abnor- malities present in ≥2 out of 20 metaphases or if the abnormalities are present in one metaphase in ≥2 assess- ments.
The first case with a deletion of 7q was reported by Gambacorti-Passeri,9 and subsequently more details were provided by several groups on occasional individual cases. Soon after, Andersen et al.10 reported on a patient who developed monosomy 7 after 12 months of imatinib therapy with BM hypoplastic signs and dysplastic fea- tures. Although CCA/Ph- abnormalities is a rare observa- tion, the risk of developing MDS or AML has not been precisely defined, and the proportion of patients with chromosome 7 abnormalities is not really known. Thus, it is important to perform studies on a large group of
CML patients developing additional clonal abnormalities. By 2011, Groves et al.5 had reviewed all cases published since 2002. The study cohort included 53 patients. The majority were in chronic phase but six had accelerated phase at the time of starting TKI. Previous treatment was interferon for 39 patients and only six patients were pre- viously untreated. Of the 53 patients, -7 was the sole abnormality in 29 patients, -7 with +8 as an additional abnormal Ph- clone in 14 patients, and del(7q) in ten patients. The chromosome 7abnormality was present in two or more metaphases in all but three patients. In the nine patients who developed AML, only one patient sur- vived despite intensive chemotherapy or allogeneic stem cell transplantation. Resolution of MDS (refractory ane- mia with ring sideroblasts) was noted in one patient after discontinuation of TKI. Based on this survey, it was sug- gested that the risk of a second malignancy with -7 was significantly higher since none of the patients with del(7q) developed MDS or AML. As AML is an important event, the risk of developing AML was analyzed. Factors influencing the onset of AML appeared to be persistence (compared to transience) of a Ph-7clone, particularly - 7sole, and a clone size of 50% or more at diagnosis; time to diagnosis of MDS/AML should also be considered. Transformation to MDS/AML was observed within six months of Ph -7 detection in 15 patients, with only one patient diagnosed at 11 months. Of the 12 patients with follow up of more than six months, none developed a second myeloid malignancy, suggesting that the risk of MDS/AML is higher within the first six months of Ph -7 detection than at later time points (P<0.0001). Karimata et al.11 reported a single case of a 60-year Japanese man who was treated for seven years with various doses of ima- tinib. He had several episodes of cytopenia, and five years after the start of imatinib, a cytogenetic analysis revealed a complete cytogenetic response but monosomy 7 was detected in 16 out of 20 cells. BM smears showed a refrac- tory anemia with multilineage dysplasia which pro- gressed to AML and death. Two additional cases of monosomy 7 out of 155 CML chronic phase patients were subsequently reported.6 The median time of the first appearance of monosomy 7 was six months. The clone of monosomy 7 persisted for eight years in the patient who achieved sustained major molecular response (MMR) and six months until BM transplantation in the second patient. More recently, the group of Cortes conducted a retrospective analysis of patients treated front line with first-, second-, and third-generation TKI.7 Among the 598 evaluable patients, 108 (18%) had CCA/Ph-. Of these, 4 patients with monosomy 7 had the worst survival.
In this issue of Haematologica, Bodet et al. provide use- ful additional information on patients who are diagnosed with -7/del(7q) abnormalities during the course of their
haematologica | 2019; 104(6)