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.