Discussion
The present patient developed lymphoma after being treatment with three different TKIs. The patient developed HGBCL after administration of bosutinib. This is a valuable case because no previous studies have reported the detailed clinical course of such a case.
The risk of secondary cancer due to TKI has been a subject of debate. Novartis reported that among 9,518 CML patients administered imatinib, the incidence of secondary malignancy was 1.16%, and that cancer onset did not increase by administration of imatinib6. This data, however, is based on spontaneous reports and it is possible that secondary cancers were under-reported. MD Anderson Cancer Center also reported that TKI does not increase the risk of cancer7, but their data included patients with diseases other than CML. Contrarily, albeit from a small sample size, Roy L et al. observed secondary cancer in 3.17 % of patients after 8-36 months of imatinib administration, and reported a particularly high risk of prostate cancer among them3. Shah BK et al. reported that the risk of cancer onset in CML before the introduction of imatinib was equal to that of healthy individuals, but that the risk of secondary malignancies in CML has increased since its introduction8. Sweden has also reported that the risk of cancer in CML patients who were administered TKI increases by approximately 1.5-fold that of the general population9. In a survey of 13,256 CML patients, Sasaki K et al. reported a 4.5 % incidence of secondary malignancies4. In this study, patients who had a history of cancer at the time of CML diagnosis and those who developed other cancers within one year of the CML diagnosis were excluded from this report. Furthermore, the 10-year risk of secondary malignancy was stable. These reports suggest that TKI may increase the risk of secondary malignancies and it is therefore necessary to cautiously observe patients receiving a TKI treatment for the onset of other cancers.
Sasaki K et al. reported 31 (0.2%) CML patients with secondary lymphoma, but their clinical courses are unknown. Table 1 showed the detailed clinical course of lymphomas that developed during TKI treatment in CML patients10-17. Among them, imatinib was the most commonly used medication, while there were no reports of patients who were treated with bosutinib. The time from the initial TKI dose to the onset of the secondary cancer was longest in our case. The outcomes of the lymphoma are unknown for case 4 and 8, while case 3 died 8 months after developing the lymphoma. Other cases responded well to chemotherapy.
Several possible mechanisms of the onset of secondary cancer in CML patients under TKI therapy may be thought possible. First, CML itself may increase the risk of cancer onset. It is possible that BCR-ABL translocation may introduce genetic instability and that progenitors of solid cancers or other hematological malignancies were already latent at the time of CML diagnosis18. However, patients who had been in long-term remission have also been observed with secondary cancer; therefore, this hypothesis alone does not fully explain the mechanisms of onset. Second, it is possible that TKI is oncogenic.In vitro studies have reported that imatinib induces irreversible chromosomal abnormalities or aberrations19. This chromosome instability may influence the development of the earliest stages of cancer20. Third, and possibly most importantly, TKI-induced immunosuppression may leave patients vulnerable to secondary cancers. Generally, patients with compromised immune systems are more prone to develop malignancies21. TKIs are known to inhibit the proliferation or function of T cells, B cells, and NK cells22, and this may decrease tumor immunity, thereby contributing to the cancer onset. Thus, as long as patients are on TKI therapy, they must be considered as being exposed to the risk of secondary malignancies. Although Epstein–Barr virus can contribute to the pathogenesis of lymphoma, particularly in compromised patients23, Epstein–Barr encoding region in situ hybridization was negative with this patient’s specimens.
There are no clear reports on the prognosis of lymphoma developed during TKI therapy. The present patient responded rapidly to initial therapy as well as most of other patients displayed in Table 1. Lymphoma arising in patients with primary immunodeficiencies is generally known to have poor a prognosis24. However, the prognosis of most of iatrogenic immunodeficiency-associated lymphomas is not poor25. Presently, the only treatment available for lymphomas resulting from TKI therapy is the same as that for de novo lymphoma. Accumulating data from more patients is needed for the development of novel therapeutic strategies for lymphomas secondary to TKI.