Case Discussion [Brief History] The 32 year-old male was a case of general health before and denied any systemic disease. This time, the patient suffered from progressive abdominal fullness since about one month ago. Besides, general weakness, malaise, exertional dyspnea was also noted. Due to the symptoms described above, the patient visited our OPD where physical examination revealed pale conjunctiva, hepatomegaly and massive splenomegaly. Besides, the initial CBC data revealed severe leukocytosis associated with anemia and thrombocytosis (WBC 187,560/ul , Hemoglobin 7.1 g/dl, Platelet 699,000/ul). Under impression of chronic myeloid leukemia, the patient admitted for further evaluation and treatment. [Laboratory Data and Special Examination] The peripheral blood smear was examined after admission revealed complete spectrum of myeloid cells. The WBC differential cont and a serial examination listed as below: CBC: WBC 185660 /ul, Hb 6.5 g/dl, PLT 575000 /ul Myeloblast 1.5%, Promyelocyte 5.0%, Myelocyte 18%        Metamyelocyte 6% Band 28%, Segment 30%, Eosinophil 4.5%, Basophil 4.0%, Monocyte 0%,Lymphocyte 3.0% Bone marrow aspiration: Microscopically revealed marked hypercellularity (>95%) with increase of megakaryocytes. The myeloid series was marked hyperplasia (M/E ratio = 10~15:1) and blasts count was 2%. Bone marrow biopsy: Consistent with CML Bone marrow chromosome: t(9;22) Bone marrow bcr-abl gene: (+) LAP score = 5 [Treatment and Course]  After the diagnosis of chronic myeloid leukemia established, the patient received initial treatment with interferon-a and hydroxyurea. Although the patient suffered from fever, chills and flu-like symptoms at initial treatment of interferon, this symptoms and signs subsided in latter course of treatment. The white cell counts decreased progressive after our treatment. Besides, the abdominal fullness also subsided after splenomegaly resolved. Due to young age of the patient, we will arrange allogeneic hematopoietic stem cell transplantation for this patient if HLA-identical sibling donor available. [Discussion] 慢性骨髓性白血病 (chronic myeloid leukemia, CML) 的發生率是1.3人每年每十萬人。有些患者可能沒有症狀而在檢康檢查發現有白血球過高的現象；其他患者則可能有疲倦、體重減輕、或者因為脾臟腫大而造成易飽食感以及左上腹痛、或者因為白血球以及血小板出現問題而造成感染、出血等現象。較少的情況下，患者可能因為白血球太高而造成hyperleukocytosis syndrome而導致心肌梗塞、腦血管病變等。至於理學檢查方面主要以肝脾腫大為主；很少部分的患者才會有lymphadenopathy或者是myeloid tumor (granulocytic sarcoma)，若出現這種情形預後會比較不好。 上述這位患者可說是相當典型的CML。由一開始白血球過高且白血球分類有各個stage的myeloid cells，理學檢查可發現有肝脾腫大，周邊血液抹片LAP score 相當低，骨髓檢查發現hypercellularity with myeloid hyperplasia且M/E ratio明顯上升；染色體檢查發現有t(9: 22) 而基因檢查也發現有 bcr-abl fusion gene。綜合上述檢查，可以確定診斷該患者唯一慢性骨髓性白血病患者。 在慢性骨髓性白血病的病生理機轉最重要的就是t(9:22) [又稱為Philadelphia Chromosome]。這個染色體轉位會造成原來位在上chromosome 9的Abelson (ABL) proto-oncogene接到chromosome 22的breakpoint cluster region (BCR) gene上，形成BCR-ABL chimeric gene。正常的ABL gene在轉錄轉譯後產生的tyrosine kinase會受到嚴密的調控；但發生t(9;22)所形成的BCR-ABL fusion gene則失去正常的調控機轉，造成tyrosine kinase過度表現的情形。在慢性骨髓性白血病患者，有 > 90% 的患者會有Philadelphia Chromosome，有 > 95% 的患者可以利用PCR的方式找到BCR-ABL gene。 慢性骨髓性白血病的病程一般可分為三個階段：Chronic phasea Accelerated phase aBlast phase。Median survival 大約是4年。在治療方面，唯一能夠根治的方式是異體造血幹細胞移植 (allogeneic hematopoietic stem cell transplantation)；因此若是患者年輕、有HLA-matched donor、身體狀況許可、並且有意願者，會建議進行造血幹細胞移植。然而，由於異體造血幹細胞移植本身是具有危險的治療，故必需在醫師以及家屬在適當的溝通討論後才進行。在藥物治療方面，傳統較常用的第一線治療包括Interferon Alpha以及Hydroxyurea。其中Hydroxyurea的優點是可以口服、價格較便宜、可以較快的達到hematologic response、毒性也較小，但缺點是沒有辦法達到cytogenetic response，對survival也沒有幫助；至於Interferon Alpha則是無法口服、價格較昂貴、沒有辦法很快的達到hematologic response、毒性也較大，但優點是有機會達到cytogenetic response，且對survival的改善也有幫助。另外，有些報告指出，若長期使用Interferon Alpha後立刻進行造血幹細胞移植會造成比較不好的預後，但若是停用Interferon Alpha三個月後再進行造血幹細胞移植則不會有此種情形。 至於新開發的藥物則有Imatinib (Gleevec, Novartis, Basel, Switzerland)，過去在開發階段時又曾經稱為CGP57148B, STI571。這是一個tyrosine kinase inhibitor可以特異性的抑制BCR/ABL fusion protein所造成的tyrosine kinase過度表現。Imatinib在臨床上顯著的療效使得 t(9;22) and/or BCR-ABL fusion gene在致病機轉扮演樞紐的角色得到進一步的確認，但其長期的療效仍須等待進一步的研究報告。 繼續教育考題 1. (B) LAP score will decrease which of the following diseases?  A Acute myeloid leukemia. B Chronic myeloid leukemia. C Hodgkin’s disease. D Polycythemia vera. E Essential thrombocytosis. 2. (C) The cytogenetic hallmark of CML: A  t(8;21) B t(15;17) C t(9;22) D inv(16) E t(4;11) 3. (D) Which is the “less” common manifestation of CML: A Splenomegaly B  Early satiety C Left upper quadrant pain or mass. D Lymphadenopathy. E Hepatomegaly. 4. (E) Which is the only curative therapy for CML: A Hydroxyurea. B  Interferon Alpha. C Leukapheresis. D Splenectomy E Allogeneic hematopoietic stem cell transplantation. 5. (A) Which is “not” the hematologic finding of CML? A Leukocytosis with myeloblast > 30 in peripheral blood. B Platelet counts almost always elevated at diagnosis. C Mild degree of normochromic normocytic anemia. D Phagocytic functions are usually normal at diagnosis and remain normal during the chronic phase. E Basophilia. 6. (B) Which of the following fusion genes will found in > 95% of CML patient? A AML1/ETO B BCR-ABL C CBFb/MYH1 D CBFa/ETO E PML/RARa 7. (C) Which of the following drugs can induce rapid hematologic responses? 1. Interferon Alpha, 2. Imatinib, 3.Hydroxyurea A 1+2 B 1+3 C 2+3 D 1+2+3 E Non of above. 8. (D) Which of the following drugs can induce cytogenetic response? 1.Interferon Alpha, 2.Imatinib, 3.Hydroxyurea A 1+2+3 B 1+3 C 2+3 D 1+2 E Non of above. 9. (E) Which of the following is “not” suitable for hematopoietic stem cell transplantation in CML patient? A Have health and histocompatible donor.  B CML patient, in chronic phase C One locus mismatched sibling donor D ABO mismatch donor E > 65 years old. 10. (A) Which of the following descriptions is “wrong”?  A The treatment of all forms of blast crisis is generally effective. B The general clinical onset of the chronic phase is generally insidious. C Some patients are diagnosed while still asymptomatic, during health screening tests. D When allogeneic SCT is not feasible, Interferon alpha is the treatment of choice. E Interferons have potent, pleiotropic biologic effects, spanning a spectrum of antiviral, Microbicidal, immunomodulatory, and Antiproliferative properties.