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Molecular Response of e19a2 BCR-ABL1 Chronic Myeloid Leukemia With Double Philadelphia Chromosome to Dasatinib
Chromosomal translocation t(9;22)(q34;q11.2) that results in BCR-ABL1 gene fusion and the Philadelphia chromosome (Ph) plays the causative role in chronic myeloid leukemia (CML).1 BCR-ABL1 protein acts as a tyrosine kinase that causes abnormal cell proliferation; thus, a BCR-ABL1 tyrosine kinase inhibitor (TKI) such as imatinib is standard treatment for CML.2,3 In addition, second-generation TKIs, including nilotinib and dasatinib, that were previously used for patients with CML who were resistant to or unable to tolerate treatment with imatinib4,5 have become available for newly diagnosed patients with CML.6,7
BCR-ABL1 fusion also causes genetic instability that may lead to additional chromosomal aberrations (ACAs) in CML.8 Major-route ACAs, which consist of a double Ph chromosome, trisomy 8, and i(17)(q10), are found in approximately 1% of patients with chronic-phase CML at diagnosis and have a significant negative impact on response to imatinib. Therefore, major-route ACAs result in disease progression from chronic phase to accelerated phase or blast crisis, and inferior overall survival. Alternatively, rare minor-route ACAs such as t(3;12) and t(4;6) are usually observed at accelerated phase or blast crisis.
A variety of BCR-ABL1 transcripts that generally correspond to the chromosomal breakpoints of the BCR have been identified.1 In more than 95% of patients with CML, BCR-ABL1 transcript is either e13a2 (b3a2) or e14a2 (b2a2), namely major BCR-ABL1, because of a breakpoint in intron 13 or 14 of BCR, respectively. Approximately 1% to 2% of CMLs show e1a2 (minor BCR-ABL1) with the breakpoint in intron 1 of BCR.9 In addition, another breakpoint in intron 19 of BCR, which gives rise to e19a2 (micro BCR-ABL1),1 encoding a 230-kDa protein, is extremely rare (0.8% to 1.6%) in CML.10 In fact, to date, only approximately 50 patients with e19a2 BCR-ABL1 have been reported in CML. Among these, 15 patients were treated with TKIs.11–22 Of these 15 patients, 14 received imatinib as a first TKI, but in general they responded poorly to imatinib, and most of them eventually required a second-generation TKI or died. To our knowledge, there have not yet been any reports of patients with e19a2 BCR-ABL1 CML who were initially treated with dasatinib. Here, we report a patient with CML who demonstrated e19a2 BCR-ABL1 with a double Ph chromosome and was successfully treated with dasatinib as first-line therapy.
A 72-year-old woman, who had undergone medical examination every 3 months since an operation for lung cancer in 2007, showed an increased peripheral WBC count (15.6 × 109/L) in early 2012, which consisted of blasts (1%), myelocytes (12%), metamyelocytes (3%), band-form neutrophils (2%), segmented neutrophils (63%), basophils (1%), eosinophils (1%), monocytes (4%), and lymphocytes (13%). Hemoglobin concentration (14.8 g/dL) and platelet count (170 × 109/L) were within normal ranges. Her serum lactate dehydrogenase had increased (818 U/L), but there were no other abnormal findings in the biochemistry examination. Neither splenomegaly nor recurrence of lung cancer was evident in systemic computed tomography. Bone marrow examination showed a proliferation of myeloid cells with 72.0% of the total proportion containing 8.4% of promyelocytes, 12.0% myelocytes, 8.0% metamyelocytes, 35.6% band-form neutrophils, and 5.6% segmented neutrophils. The proportion of eosinophils had increased (8.0%), but the proportion of blasts (2.4%) and basophils (1.6%) had not. These findings were consistent with chronic-phase CML. Both single BCR-ABL1 fusion (14%) and dual BCR-ABL1 fusions (82%) were detected in peripheral interphase neutrophils (Fig 1A, fluorescent in situ hybridization with probes for BCR and ABL1). Bone marrow cells showed 47,XX, t(9;22)(q34;q11.2), +der(22)(9;22) in all 20 of the analyzed mitotic cells (Fig 1B, banding chromosomal analysis without addition of mitogen). Quantitative real-time polymerase chain reaction of peripheral-blood cells detected 1,000,000 copies/μg RNA of e19a2 BCR-ABL1 transcript, which was confirmed by direct sequencing. Additional ABL1 mutation was not found in the screening assay. The patient was treated with dasatinib and achieved a complete cytogenetic response at 6 months. After 12 months, the patient's e19a2 BCR-ABL1 transcript decreased to 96 copies/μg RNA, with a 0.0094% of BCR-ABL1/ABL1 ratio, indicating a major molecular response.
Fig 1.To our knowledge, there have been 16 patients with CML with the e19a2 BCR-ABL1 transcript, including our patient, who were treated using TKIs (Table 1). Although the data may be biased because these cases were sporadically reported, imatinib did not provide a consistent molecular response for these patients (patients 1 through 13 and 15), suggesting that the effect of imatinib is probably insufficient for the vast majority of patients with e19a2 BCR-ABL1 CML. As a first-line treatment, nilotinib was used for one patient (patient 14). This patient achieved a major molecular response 17 months after starting treatment.21 However, our patient achieved a major molecular response 12 months after beginning dasatinib. Subsequently, although nilotinib was used for three patients with imatinib failure (patients 11, 13, and 15), the effect was limited, with an incomplete rather than complete cytogenetic response. In contrast, both of the patients for whom dasatinib replaced imatinib after treatment failure (patients 9 and 12) subsequently achieved a major molecular response. Therefore, dasatinib might be superior to nilotinib for the treatment of e19a2 BCR-ABL1 CML, in particular in patients who experienced treatment failure with imatinib. However, the number of patients reported as having e19a2 BCR-ABL1 CML has been insufficient to determine whether nilotinib or dasatinib is better for this disease entity. In addition, treatment with dasatinib as the third TKI was not successful in two patients who experienced treatment failure with both imatinib and nilotinib, possibly because of either ACA (patient 15) or ABL1 mutation (patient 11).
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| Patient No. | Age (years) | Sex | Disease Status | Major-Route ACA* | ABL1 Mutation | Pretreatment | TKI | Response | Reference | |
|---|---|---|---|---|---|---|---|---|---|---|
| At Diagnosis | At Start of TKI | |||||||||
| 1 | 23 | F | BC | BC | None | None | Imatinib | CCyR (→ SCT) | 11 | |
| 2 | 47 | F | CP | CP | None | None | Imatinib | CCyR | 11 | |
| 3 | 55 | M | CP | CP | None | None | Imatinib | CCyR | 11 | |
| 4 | 69 | F | AP | AP | Double Ph | HU | Imatinib | NR (intolerance) | 12 | |
| 5 | 38 | M | CP | AP | None | HU | Imatinib | NR | 13 | |
| 6 | 41 | M | CP | AP | None | HU | Imatinib | CCyR | 14 | |
| 7 | 45 | F | CP | CP | Double Ph† | HU, IFN | Imatinib | No CyR | 14 | |
| 8 | 36 | M | CP | BC | Double Ph | HU, IFN | Imatinib | MCyR (→ SCT) | 15 | |
| 9 | 72 | F | CP | CP | None | Y253H‡ | HU | Imatinib → dasatinib | 1st MMR with imatinib, 2nd MMR with dasatinib | 16 |
| 10 | 85 | F | CP | CP | Double Ph,‡ complex‡ | None | Imatinib | No CyR | 17 | |
| 11 | 78 | F | CP | AP | +8§ | E255K,¶ T315I‖ | Ara-C, IFN | Imatinib → nilotinib → dasatinib | mCyR with each TKI | 18 |
| 12 | 63 | M | CP | CP | Double Ph | G250E§ | None | Imatinib → dasatinib | No CyR with imatinib, MMR with dasatinib | 19 |
| 13 | 34 | F | CP | CP | i(17)(q10)‡ | E355G‡ | HU | Imatinib → nilotinib | 1st MCyR with imatinib, 2nd MCyR with nilotinib | 20 |
| 14 | 26 | M | CP | CP | Double Ph | None | Nilotinib | MMR | 21 | |
| 15 | 80 | M | CP | CP | Double Ph‖ | None | Imatinib → nilotinib → dasatinib | Intolerance with nilotinib, MCyR with dasatinib | 22 | |
| 16 | 72 | F | CP | CP | Double Ph | None | Dasatinib | MMR | Our patient | |
Abbreviations: ACA, additional chromosomal abnormality; AP, accelerated phase; Ara-C, cytarabine; BC, blast crisis; CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; CP, chronic phase; CyR, cytogenetic response; HU, hydroxyurea; IFN, interferon; MCyR, major cytogenetic response; mCyR, minor cutogenetic response; MMR, major molecular response; NR, no response; Ph, Philadelphia chromosome; SCT, stem-cell transplantation; TKI, tyrosine kinase inhibitor.
*Major-route ACA includes double Ph, +8, and i(17)(q10).
†Additional abnormality occurred while receiving HU/IFN.
‡Additional abnormality occurred while receiving imatinib.
§Additional abnormality occurred while receiving Ara-C/IFN.
‖Additional abnormality occurred while receiving dasatinib.
¶Additional abnormality occurred while receiving nilotinib.
In patients with e19a2 BCR-ABL1 CML treated with TKIs, eight patients (50%), including five patients at diagnosis (patients 4, 8, 12, 14, and 16 [our present patient]) and 3 patients during the clinical course (patients 7, 10, and 15), have shown the double Ph chromosome (Table 1). In addition, two other patients developed different major-route ACAs during their clinical courses: +8 in patient 11 and i(17)(q10) in patient 13. A previous study of e19a2 BCR-ABL1 CML that included patients in the pre-TKI era also showed high incidences of ACAs, including the double Ph chromosome.17 In contrast, it has been reported that major-route ACAs are observed in less than 5% of patients at diagnosis in CML with major (e13a2 or e14a2) BCR-ABL1.8 Hence, high incidences of major-route ACAs, especially double Ph chromosome, are likely to be associated with pathogenesis of e19a2 BCR-ABL1 CML. According to Fabarius et al,8 major-route ACAs significantly correlate with longer time to achieve major molecular response with imatinib and shorter duration of survival in CML with major BCR-ABL1. Strikingly, among patients with e19a2 BCR-ABL1 CML who were treated with imatinib, six of nine patients without ACAs at the start of imatinib treatment (patients 1 through 3, 5, 6, 9, 10, 13, and 15), but none of the five patients with ACAs (patients 4, 7, 8, 11, and 12) achieved complete cytogenetic response (Table 1). This fact suggests that occurrence of ACAs contributes to poor response of e19a2 BCR-ABL1 CML to imatinib, as well as CML with major BCR-ABL1.8 However, even if the patients achieved complete cytogenetic response, most of them did not achieve a major molecular response with imatinib in e19a2 BCR-ABL1 CML. The cause of this resistance of e19a2 BCR-ABL1 CML to imatinib should be investigated in the future, but clonal evolution may in part explain the mechanism in some patients who developed a mutation in ABL1 (patients 9, 12, and 13). In contrast, a major molecular response in patient 14 and in our present patient may indicate that second-generation TKIs rather than imatinib have the potential to overcome such resistance, although clonal evolution can also arise while using second-generation TKIs, as in patient 11.
In conclusion, our present case indicates the efficacy of dasatinib for e19a2 BCR-ABL1 CML. Studies comparing dasatinib with nilotinib or later-generation TKIs for this rare type of CML should be performed in future.
The author(s) indicated no potential conflicts of interest.
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