Emergence of chronic myelogenous leukemia during treatment for essential thrombocythemia
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- Mizutani, S., Kuroda, J., Shimizu, D. et al. Int J Hematol (2010) 91: 516. doi:10.1007/s12185-010-0502-3
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A 72-year-old male patient was initially diagnosed with essential thrombocythemia (ET), a Philadelphia chromosome-negative (Ph1−) chronic myeloproliferative disorder (CMPD), and was treated with hydroxyurea (HU). After 9 years of diagnosis of ET, his peripheral leukocytes gradually increased, while his platelet count showed a decrease. Bone marrow analysis disclosed Ph-positive chronic myelogenous leukemia (CML) in the chronic phase. Administration of imatinib mesylate (IM), a Bcr–Abl tyrosine kinase inhibitor (TKI), induced complete hematologic response in a month, but was discontinued after 4 months because of Grade 3 pleural effusion (PE). The treatment was switched to nilotinib which successfully induced a complete cytogenetic response (CCyR) after 5 months of TKI therapy and resolved the PE. Despite CCyR, however, ET recurred. Since then, the patient has been treated for 8 months with a combination of nilotinib and HU which has successfully controlled both CML and ET. This report includes a review of the characteristics of 15 reported cases with co-occurrence of CML and Bcr–Abl-negative CMPDs, including ours. Although rare, care needs to be taken since, despite the often similar clinical features of the two diseases, they require completely different treatments.
KeywordsChronic myelogenous leukemiaEssential thrombocythemiaChronic myeloproliferative disorderTyrosine kinase inhibitor
Chronic myeloproliferative diseases (CMPDs) are classified into two major categories, Philadelphia chromosome (Ph1)-positive (Ph1+) chronic myelogenous leukemia (CML) and Ph1-negative (Ph1−) disorders, such as polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Although approximately 1–11% of the latter disorders transform into acute myelogenous leukemia (AML) in their late clinical phase regardless of JAK2V617F mutational status or leukocyte counts at diagnosis [1–5], the coexistence of or more CMPDs is extremely rare and only 14 cases with CML and Bcr–Abl-negative (Bcr–Abl−) CMPDs have been reported previously [6–18]. Here, we report a case with CML emerging after a 9-year history of ET, who was successfully treated with a combination of Bcr–Abl tyrosine kinase inhibitors (TKIs) and hydroxyurea (HU). We also review previous cases with Bcr–Abl− CMPDs co-occurring with CML.
2 Case report
Bone marrow analysis findings
ET recurrence CML in CCyR
Ph1 + metaphase in BM
The co-emergence of CML and Bcr–Abl− CMPDs is extremely rare with only 14 previous cases reported [6–18], so that there is scant information on clinical outcomes and treatment strategies for this occurrence. For this reason, we review here CML accompanied by CMPDs in terms of both clinical features and treatments.
Of the 15 cases of co-occurrence of CML and Bcr–Abl− CMPD, including ours, CMPD preceded CML in 11 cases, and in 3 they were diagnosed simultaneously at the initial diagnosis. Even in a unique case reported by Krämer et al. in which the diagnosis of myelofibrosis was attained after 3 months treatment with IM for CML, JAK2V617F mutation was retrospectively identified in leukocytes at the diagnosis of CML, suggesting the presence of CMPD clones before the diagnosis of CML . Accordingly, in none of the cases did Bcr–Abl− CMPD develop after CML. The type of CMPD preceding CML was ET in five cases, MF in six and PV in four each. The median age of the onset of CML in those patients was 64.0 ± 13.2 years which is somewhat older than usual for CML. No recurrent chromosomal abnormalities were observed in ten cases examined for such abnormalities when CMPD was diagnosed, and JAK2V617F mutation was identified in six of the ten patients examined for this mutation. Eleven had been treated with HU and one with 32P before the emergence of CML. Generally, 32P exposure may increase the risk for of secondary AML, while HU does not , but the effect of these treatments on secondary leukemogenesis, such as in CML, remains unclear. Finally, the time until the development of CML from the diagnosis of other CMPDs in the 11 cases of non-simultaneous occurrence varied widely from 2 to 18 years (mean ± standard deviation 9.0 ± 5.0 years). These findings indicate that patients affected by CML following CMPD are unlikely feature any particular clinical background which may help in predicting the emergence of CML during the treatment for CMPD.
As for treatment, IM was found to be effective for CML accompanied by CMPD. For the 13 patients for whom data are available, IM treatment achieved major molecular response (MMR) in 5, the 2-log reduction in bcr–abl transcripts in 1, CCyR in 4, and partial cytogenetic response (PCyR) in 3 patients. However, the outcome for TKI treatment of the preceding Bcr–Abl− CMPDs was not successful in all cases. Of the 11 cases for whom data are available, CMPDs were controlled successfully with TKI treatment in 5 cases, but recurred in 6. In our case, thrombocythemia recurred after the switch to nilotinib treatment when the patient had achieved CCyR for CML. These findings suggest two hypotheses to account for the co-emergence of CML and Bcr–Abl− CMPDs. According to the first hypothesis, the off-target effect of IM, such as on c-KIT, may suppress the expansion of tumorigenic Bcr–Abl− clones in some cases including ours, while nilotinib, with an off-target effect that is less than that of IM, allows for the expansion of Bcr–Abl− clones and the subsequent thrombocythemia as seen in our case. The other hypothesis is that long-term treatment with TKIs causes the suppression of Ph1+ clones, which then creates space for the re-expansion of Bcr–Abl− CMPD clones in BM. The two mechanisms may co-exist, and whether CMPD clones re-expand or not following TKI treatment may depend on the balance of the off-target kinetics of TKI treatment and the proliferation potency of CPMD clones, which may differ from case to case. When Bcr–Abl− CMPDs recur as in our case, the additional treatment with TKI may thus be required. Indeed, the addition of HU to TKI was successful in two cases those experience the re-emergence of CMPD following TKI treatment, including ours .
In conclusion, this report is the first of a patient with ET accompanied by CML who was successfully treated with a combination of nilotinib and HU. We also reviewed other cases of CML co-occurring with Bcr–Abl− CMPDs. Although the co-emergence of CML during treatment for Ph1− CMPDs is rare, care needs to be taken since, despite the often similar clinical features of the two diseases, they require completely different treatments.
We are grateful to Ms. M. Goto and Ms. R. Tanaka for their excellent technical supports. This work is partly supported by the grant from Japan Leukaemia Research Fund (to J.K.).