ORIGINAL ARTICLE
Additional chromosome abnormalities in chronic
myeloid leukemia
額
額外
外染
染色
色體
體變
變化
化於
於慢
慢性
性骨
骨髓
髓性
性白
白血
血病
病之
之表
表現
現
Hui-Hua Hsiao
a,b,c, Yi-Chang Liu
a,b,c, Hui-Jen Tsai
a,c, Jui-Feng Hsu
a,
Wen-Chi Yang
a,c, Chao-Sung Chang
a,b, Sheng-Fung Lin
a,b,*
蕭惠樺a,b,c,劉益昌a,b,c, 蔡慧珍a,c,許瑞峰a,楊文祺a,c, 張肇松a,b,林勝豐a,b,*
a
Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
b
Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
c
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Received 29 June 2010; accepted 21 September 2010
Available online 10 February 2011
KEYWORDS Additional chromosome abnormality; BCR-ABL; Chronic myeloid leukemia; Variant Philadelphia chromosome 關鍵詞 慢性骨髓性白血病; 額外染色體變化; 變異的費城染色體; BCR-ABL
Abstract The Philadelphia (Ph) chromosome and/or Breakpoint cluster region-Abelson leukemia virus oncogene transcript are unique markers for chronic myeloid leukemia (CML). However, CML demonstrates heterogeneous presentations and outcomes. We analyzed the cyto-genetic and molecular results of CML patients to evaluate their correlation with clinical presen-tations and outcome. A total of 84 newly diagnosed CML patients were enrolled in the study. Patients were treated according to disease status. Bone marrow samples were obtained to perform cytogenetic and molecular studies. Clinical presentations, treatment courses, and survival were reviewed retrospectively. Among 84 patients, 72 had chronic phase and 12 had accelerated phase CML. Cytogenetic study showed 69 (82.1%) with the classic Ph chromosome, 6 (7.2%) with a variant Ph chromosome, and 9 (10.7%) with additional chromosome abnormalities. Fifty-four (64.3%) cases harbored b3a2 transcripts, 29 (34.5%) had b2a2 transcript, and 1 had e19a2 transcript. There was no difference in clinical presentations between different cytoge-netic and molecular groups; however, additional chromosome abnormalities were significantly associated with the accelerated phase. Imatinib therapy was an effective treatment, as measured by cytogenetic response, when administered as first- and second-line therapy in chronic phase patients. Survival analysis showed that old age, additional chromosome abnormal-ities, high Sokal score, and no cytogenetic response in second-line therapy had a significant poor impact (p< 0.05). In conclusion, we presented the cytogenetic and molecular pattern of CML patients and demonstrated that the additional chromosome abnormality was associated with poor outcome.
* Corresponding author. Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, 100 Shih-Chuan 1stRoad, Kaohsiung 807, Taiwan.
E-mail address:[email protected](S.-F. Lin).
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : h t t p : / / w w w . k j m s - o n l i n e . c o m
1607-551X/$36 Copyrightª 2011, Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.kjms.2010.09.001
摘 摘要要 慢性骨髓性白血病通常帶有獨特的標記，包括費城染色體和BCR-ABL的基因，然而此病之 臨床表現及預後卻往往有很大的差異。因此我們分析慢性骨髓性白血病病患之染色體及基因檢查 之結果，來看是否這些資料和臨床表現及預後有相關。共有84位新診斷的慢性骨髓性白血病病人 進行分析，而這些病人的治療是依據病患的狀況予以治療。染色體及基因檢查是由病患的骨髓檢 體所做之檢查，而病患的臨床表現、治療狀況及預後是由病歷資料回顧所得。於84位病人中有72 位是屬於慢性期，有12位是屬於加速期。染色體檢查中有69位 (82.1%)是屬於標準的費城染色 體，有6位 (7.2%)是屬於變異的費城染色體，有9位 (10.7%) 是屬於額外染色體變化。基因檢查中 有54位(64.3%)是屬於b3a2，有29位(34.5%)是屬於b2a2，有1位是屬於e19a2。病患的臨床表現和 不同組的染色體及基因並無差別，但是額外染色體變化卻和病患的加速期有相關。而Imatinib對 慢性期病患於一線及二線的治療均有不錯之反應。生存分析中發現年紀愈大、有額外染色體變 化、有較高的Sokal分數、對二線的治療反應不佳者有有意義的負面影響(p<0.05)。我們於此報告 中顯示了慢性骨髓性白血病病患之染色體及基因變化，且顯示出額外染色體變化對慢性骨髓性白 血病有不良之影響。
Copyrightª 2011, Elsevier Taiwan LLC. All rights reserved.
Introduction
Chronic myeloid leukemia (CML) is characterized by the presence of Philadelphia (Ph) chromosome, a result of a balanced translocation between chromosomes 9 and 22, that is, t(9;22)(q34;q11)[1,2]. The translocation results in the formation of the chimeric oncogene, Breakpoint cluster region-Abelson leukemia virus oncogene (BCR-ABL), encoding the protein p210BCR-ABL[3e5]. Despite the pres-ence of unique cytogenetic and molecular hallmarks, CML demonstrates heterogeneous clinical presentations and outcomes[6]. Patients show variable survival from several years to decades and also respond differently to the medications. In addition, the heterogeneous characteristics of CML are also apparent at cytogenetic and molecular levels [6,7]. Most CML patients harbor the classic Ph; however, 5%e10% of patients have variant translocations in which at least a third chromosome is involved in the rear-rangement[8e10]. Additionally, depending on the different breakpoints of the BCR gene, most CML cases harbor a fusion oncogene comprising either the b3a2 or b2a2 transcripts[4,11].
Although some studies demonstrated that the diversities in cytogenetic and molecular levels might explain the heterogeneities of CML patients in some respects, the results are still equivocal [6,12e15]. In this study, newly diagnosed CML patients in our hospital were analyzed to see whether diversity at the cytogenetic and molecular levels was correlated with clinical features and outcome.
Materials and methods
Patients
From January 2001 to January 2010, a total of 84 newly diag-nosed CML patients were treated in our hospital and enrolled in the study. The diagnosis of CML was established on the basis of bone marrow examination, supported by cytogenetic, molecular studies, and low peripheral blood leukocyte alkaline phosphatase activity. The disease status was classified into chronic phase (CP) and accelerated phase (AP), defined as the presence of at least 15% blasts, 30% blasts plus promyelocytes in the blood or marrow, at least 20% peripheral basophils, or
thrombocytopenia unrelated to treatment[16]. Patients were treated according to the status of the disease with cytotoxic agents, including hydroxyurea, interferon-alpha, cytarabine, imatinib mesylate, and/or allogeneic stem cell transplant (SCT). Cytogenetic response (CgR) was defined as 0%e35% of cells with Ph chromosome in the follow-up examination. Clinical presentations, treatment courses, and survival dura-tion were reviewed from the medical records retrospectively. Cytogenetic study
Cytogenetic studies were obtained from bone marrow samples of the patients at the time of diagnosis. The study was performed from unstimulated specimens by Giemsa-banding method. The results were identified according to the Human System for Cytogenetic Nomenclature.
Molecular study
BCR-ABL transcript was detected by standard reverse tran-scriptase polymerase chain reaction (RT-PCR) [17]. Briefly, RNA was extracted from Ficoll-separated mononuclear cells from the bone marrow specimens. RT-PCR was performed with standard technique. The resulting fragments were separated and identified by 3% gel electrophoresis and visualized by ethidium bromide stain. Different types of the transcript were identified from the electrophoresis as reported.
Statistical analysis
The results were analyzed by SPSS version 11.5 (SPSS Inc., Chicago, IL, USA) for Windows. Chi-squared test was used to test the categorical variables. Continuing variables were compared by the t-test. The Kaplan-Meier method was used for survival analysis and the differences between each group were compared by the Long-rank test. All living patients were censored in January 2010 or at the date of last visit. A p value of less than 0.05 was considered as statistically significant.
Results
A total of 84 CML patients were enrolled in the study, including 51 males and 33 females (Table 1). Twelve cases (14.3%) were
in the AP in the diagnosis and other 72 (85.7%) were in CP. Forty-two CP patients received cytotoxic agents as the first-line treatment resulting in no CgR and 3 mortalities; whereas 29 of other 30 CP patients with imatinib therapy achieved CgR. Forty patients, 39 from cytotoxic group and 1 from the ima-tinib group, received second-line therapy with imaima-tinib (22 patients) and SCT (18 patients). Sixteen of the 22 patients who had imatinib as second-line therapy achieved CgR, whereas 16 of the 18 SCT patients had CgR. Among 12 AP patients, 3 had cytotoxic agents without a CgR. Other nine patients with imatinib plus cytotoxic agents as first-line therapy showed three CgR in the follow-up.
Cytogenetic and molecular results
All patients were positive for BCR-ABL transcripts, 54 cases (64.3%) harbored b3a2 transcripts, whereas 29 cases (34.5%) had b2a2 transcript and 1 case had e19a2 transcript (Table 1). The different molecular type had no significant difference in gender, age, white cell count, hemoglobin level and platelet count, cytogenetic subtype and disease status.
In these patients, 69 (82.1%) cases showed classical Ph chromosomes, whereas 6 patients (7.1%) had variant Ph
chromosome and other 9 (10.7%) patients harbored additional chromosome abnormalities at the time of diagnosis (Tables 1 and 2). Four out of nine patients in additional group were in AP at the diagnosis. Compared with classical Ph group, patients with additional chromosome abnormalities were associated with AP significantly (7/69 in classical Ph group vs. 4/9 in additional group; pZ 0.023) and have a trend of transformation from CP to AP (pZ 0.096). Among six cases with variant Ph, only one case showed AP in the diagnosis. There was no difference in gender, age, white cell count, hemoglobin level, platelet count, disease status and survival between variant, additional and classical groups.
Outcomes
With a mean follow-up of 40.8 months, 13 mortalities were noted, including 1 car accident (Table 1). Patients in AP were significantly associated with poor survival (pZ 0.0137), whereas therapy with imatinib showed a borderline benefit (pZ 0.0541) in these patients. In CP patients, old age, additional chromosome abnormality, high Sokal score, and no CgR in second-line therapy had poor impact on survival significantly by univariable analysis Table 1 Clinical features of the patients (nZ 84)a
Male/female 51/33 (60.7%/39.3%)
Age, yr 41.8 (13e81)
White cell count (109/L) 138,789 (11,400e968,000)
Hemoglobin (g/dL) 10.1 (6.5e14.2)
Platelet count (109/L) 409,158 (87,000e2,509,000)
Phase Accelerating phase 12 (14.3%) Chronic phase 72 (85.7%) Cytogenetics Classical 69 (82.1%) (7 AP) Variant 6 (7.2%) (1 AP) Additional 9 (10.7%) (4 AP) Molecular b3a2 54 (64.3%) b2a2 29 (34.5%) e19a2 1 (1.2%) Treatment Chronic phase (nZ 72) First-line therapy
Cytotoxic agents 42 No CgR (3 expired)
Imatinib 30 29 CgR (1 expired because of car accident)
Second-line therapy
Imatinib 22 16 CgR (4 expired)
SCT 18 16 CgR (1 expired)
Accelerating phase (nZ 12) First-line therapy
Imatinibþ cytotoxic agents 9 3 CgR (2 expired)
Cytotoxic only 3 No CgR (2 expired)
a Data presented as mean (range) or n (%).
(Table 3). However, none of them reached a statistically significant difference on survival by the multivariable analysis. Compared with cytotoxic therapy, imatinib therapy showed a significant higher CgR (pZ 0.028) as the first-line therapy in CP patients and the response of ima-tinib was higher in the first-line than second-line therapy (93.1% vs. 72.7%; pZ 0.048).
Discussion
Although most CML patients harbor unique hallmarks, such as the Ph chromosome and/or the BCR-ABL fusion transcript [1e6], they demonstrate heterogeneous characteristics in clinical presentations and outcomes [6,7]. Some studies showed that the heterogeneity might contribute with the diversity at the molecular and cytogenetic levels, but
other reports did not concur with it[6,12e15]. In our study, we report the clinical presentations of CML and showed that the additional chromosome abnormalities at diagnosis are associated with poor outcomes and a high frequency in AP.
The prognostic impact of clonal evolution in CML patients during follow-up is well established, which is highly associ-ated with disease progression[9,18e20]. In contrast, the role of additional chromosome abnormality at diagnosis is still uncertain [21,22]. However, the fact that many patients (four of nine) with additional abnormality were at AP at diagnosis and three of the other five patients suffered from transformation to AP in the follow-up suggested that the additional chromosome was associated with the advanced status of CML[19,23]. Furthermore, our study also demon-strated that additional chromosome abnormalities had a significant impact on survival in CP patients. It concurred with previous reports and implied that additional chromo-some abnormalities at diagnosis should be taken into consideration in the outcome of CML[22,24e28].
Some reports suggested that patients with variant Ph chromosomes might have a worse outcome, especially when the 50-ABL region was deleted[7,29e31]. However, our data did not support this result. It might come from the fact that four of these six patients underwent SCT later, which might have some positive effect on the prognosis[32,33]. Our data also could not identify any significant differences in the white cell count, hemoglobin level, platelet count, disease status, and survival between different types of BCR-ABL transcript.
Although this is a retrospective study, our data demon-strated that imatinib is an effective therapy with a high response rate in both first- and second-line therapy [16]. The late CP after initial first-line treatment might contribute to the inferior response of imatinib in second-line therapy [22]. Our results also showed that CgR in Table 2 Characters of nonclassic Philadelphia chromosomes
No Chromosome result Disease
status First-line therapy Second-line therapy Survival (mo) Variant Philadelphia chromosome
1 46,XY,t(3;22)(p24;q11)[8] CP Cy SCT 99 2 46,XY,t(9;9;22)(p13;q34;q11)[20] CP Cy SCT 46 3 46,XY,t(9;22;12)(q34;q11;q13)[20] CP Cy SCT 44 4 46,XX,t(9;22;15)(q34;q11;q24)[20] CP Cy SCT 45 5 46,XY,t(9;22;14)(q34;q11;q23)[20] CP Cy Imatinib 18 6 46,XY,t(4;9;22)(q21;q34;q11)[19] AP Imatinib - 20
Additional chromosome abnormalities
7 46,XY,t(9;22)(q34;q11),ins(19)(q13.3:q13.4)[14] CP Cy Imatinib 44a
8 47,XY,t(9;22)(q34;q11),þPh[17]/48,XY, idem,þ8[3] CP Cy Imatinib 40a
9 46,XX,t(9;22)(q34;q11)[5]/46,XX,idem,der(1)(q?)[10] AP Cy - 10a 10 47,XY,t(9;22)(q34;q11),þPh[5]/45-47, XY,idem,-17[15] AP Cy - 16a 11 46,XY,t(9;22)(q34;q11),t(2;3)(p25;p21)[10] CP Cy Imatinib 63 12 46,XY,t(9;22)(q34;q11)[15]/47,XY,idem,þPh[5] CP Cy SCT 58 13 46,XY,t(2;12)(p11;p11),t(3;5)(q12;p15),t(9;22)(q34;q11)[5] CP Cy 36a 14 46,XY,t(9;22)(q34;q11)[17]/46,XY,idem,t(2;21)[3] AP Imatinibþ Cy - 23a 15 46,XY,t(9;22)(q34;q11)[11]/46,XY,idem,þPh,-7[9] AP Imatinib - 26 a Patient died.
APZ accelerated phase; CP Z chronic phase; Cy Z cytotoxic agents; SCT Z stem cell transplant.
Table 3 Statistic result of patients in chronic phase (nZ 72) Characters p Age (>60 yr) 0.0483a Gender 0.8335 WBC (>100,000 109/L) 0.6587 Platelet count (>500,000 109/L) 0.4309 Anemia (Hg<12 g/dL) 0.5930 Additional chromosome 0.0070a
Molecular type (b3a2 vs. b2a2) 0.0713
First-line therapy (imatinib vs. cytotoxic agents) 0.5688
CgR in first-line therapy 0.1658
Second-line therapy (imatinib vs. SCT) 0.2009
CgR in second-line therapy 0.0010a
High Sokal risk 0.0291a
a Significant difference with p< 0.05.
second-line therapy had a survival benefit in CP patients. This might result from patients having an effective salvage therapy, with either imatinib or SCT, after first-line therapy. The survival benefit of imatinib compared with SCT is still unclear[32e34]. Our limited data also could not identify the survival difference.
In summary, we presented the clinical presentations, cytogenetic results, molecular data, and outcomes of 84 CML patients. The distribution of cytogenetic and molecular results was similar to that in other populations and there was no difference in clinical presentations between different cytogenetic and molecular groups. However, additional chromosome abnormality at diagnosis was associated with poor outcome because of high frequency in AP patients and a worse survival in CP patients, whereas variant Ph chro-mosome had no impact on the clinical presentations and outcomes. Imatinib therapy was an effective treatment with a high response rate in either first- or second-line therapy. However, further prospective studies about the role of additional chromosome in the era of imatinib are warranted to draw more obvious conclusions.
Acknowledgments
This work was supported by a grant from KMU 93 (M093011) from Kaohsiung Medical University, Taiwan. The authors are thankful for the help from Cytogentic Laboratory of Kaoh-siung University Hospital for the cytogenetic results.
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