January 12, 2011

10 Years old Malay Girl with a Rare Chronic Myeloid Leukemia with Blast Crisis.

By: Muhamad Na’im B. Ab Razak

10 years old Malay girl presented with history of prolong cough for 1 month duration with mild viral upper respiratory tract infection. The fever was on and off in nature with remittent in pattern, each episode about 3-4 days and resolve with syrup paracetamol. The fever also associated with constitutional symptoms like lethargy and loss of appetite but no loss of weight. A month later, patient presented with symptomatic anemia and thrombocytopenia and was transfused with 2 pack of blood. On examination, she was noted to have huge splenomegaly and mild hepatomegaly. Multiple lymph nodes were palpable at cervical, submandibular, supraclavicular and bilateral inguinal region. Multiplex RT-PCR for BCR-Abl gene is positive and suggestive of chronic myeloid leukemia. HLA typing was done and compatible with the youngest sisters. After two week of admission, patient was discharged with tablet Hydroxyurea 500 mg daily with monthly follow up. Ophthalmology and neuro review was done but uneventful. Four months later, during follow up at the clinic, Full blood count shows hyperleucocytosis with bicytopenia. However patient was asymptomatic for anemia. Full blood film was done and show presence of 57% blast cell which are large in size, moderate cytoplasm and prominent nucleoli. Immunophenotyping of bone marrow aspiration shows finding of blast positive for CD 34, HLA-DR, CD117, CD13, CD33, CDA, CD7 and CD2. Diagnosis of Chronic Myeloid Leukemia with Blast Crisis was made and patient was scheduled for chemotherapy.


Cancer describes more than hundred of clinical entity where there is the uncontrolled growth and spread of cells. It can affect almost any part of the body. The growths often invade surrounding tissue and can metastasize to distant sites [WHO] Cancer is a leading cause of death worldwide: it accounted for 7.4 million deaths (around 13% of all deaths) in 2004. [WHO] Deaths from cancer worldwide are projected to continue rising, with an estimated 12 million deaths in 2030.[WHO] In Malaysia, malignant neoplasms is the third cause of death in ministry of Health Malaysia Hospitals in 2006 after septicemia and disease related to heart and pulmonary circulation. A total of 21,773 cancer cases were diagnosed among Malaysians in Peninsular Malaysia in the year 2006 and registered in the National Cancer Registry [MAS Cancer Statistic, 2006]

Cancer is rare in children under 15, compared to adults; but cancer patterns at a young age present peculiar characteristics and deserve separate analysis. [UICC 2006] Malignancies of the hematopoietic system are the largest subgroup of childhood cancers world widely, accounting for 30% to 60% of all tumors [UICC 2006] and this is also same in Malaysia where the most frequent cancers in children (0-14 years old) was leukaemia [MAS Cancer Statistic, 2006]. Next on line are tumors of brain and nervous system, bone and liver. Two-thirds of lymphatic malignancies in children are leukaemias, the majority of which are acute lymphoblastic leukaemia (ALL), followed by acute myeloid leukaemia (AML). Chronic myeloid leukaemia (CML) is consistently rare everywhere.[UICC 2006]

In an audit of 803 patient attending hematology-oncology outpatient clinic in general Hospital Kuala Lumpur, 730 patients have oncological problem and the rest having hematological problem. The age ranging from 2 months to 28 years with median age of 6 years. Malay race constitute of 66% of the patient followed with Chinese (23%), India (10%) and other races (1%). Common oncological patient including leukemia, lymphoma, retinoblastoma, Wilm's tumor and germ cell tumor. 6 (0.8%) patients develops second malignant neoplasm. for the hematological problem, 60% had platelet disorder (Chronic immune thrombocytopenic purpura), 24% had bone marrow failure and 16% had red cell disorder. out of all patient, only 13 children have CML/ juvenile myelomonocytic leukemia.

As it names imply, leukemia can simply be defined as a neoplasm of the white blood cells. It arises when an immature blood cell in the bone marrow (progenitor cell) develops uncontrollably and suppresses the production of healthy blood cells. The unregulated proliferating cells usually replace normal marrow, interfere with normal marrow function, may invade other organs and eventually cause death if untreated [Chin Yuet Meng, 2001]. Leukemia can be classified into four types; acute and chronic leukemia, which are further subdivided into lymphoid or myeloid [A.V. Hoffbrand et al, 2006].

CML had been traditionally considered as part of chronic myeloproliferative disorder. As the emphasis on Philadelphia Chromosome became more prominent, CML evolved into its own entity defined by the translocation t(9:22) whereas the remaining disorders not associated with the translocation remain as part of MPD [MAS CPG, 2006].

Philadelphia chromosomes were first observed by Nowell and Hungerford in 1960 at the city of Philadelphia in which the name come from. It results from the reciprocal translocation of genetic materials between chromosome 9 and 22, t (9; 22) (q34; q11). [MK Zahry & Ravindran A, 2008] A major portion from chromosome 22 gets translocated to chromosome 9 and a minor portion from chromosome 9 gets translocated to chromosome 22. During this reciprocal translocation, the ABL gene located on chromosome 9 fuses with the BCR gene located on chromosome 22 and the molecular consequence is the creation of the fusion gene BCR/ABL, which encode a p210 fusion protein, which is an oncogenic protein that localizes to the cytoskeleton and displays an upregulated tyrosine kinase activity. This modified protein BCR/ABL causes CML by phosphorylating numerous downstream effectors of cell proliferation and cell survival and consequently cell transformation. [MK Zahry & Ravindran A, 2008]

The natural course of the disease is biphasic or triphasic. An initial indolent chronic phase eventually evolves into a more aggressive disease phase: accelerated phase (AP) and blastic phase disease/blast crisis (BC) [Alistair G. Reid et al, 2009]. Most patients with CML present in the chronic phase, characterized by splenomegaly and leukocytosis with generally few symptoms. [Maurie Markman, 2009].This phase is easily controlled by medication. The major goal of treatment during this phase is to control symptoms and complications resulting from anemia, thrombocytopenia, leukocytosis, and splenomegaly. [Maurie Markman, 2009].

CML-BC resembles acute leukemia and characterized by presence of at least 20% blasts in peripheral blood or bone marrow, large aggregates or clusters of blasts in the bone marrow trephine biopsy (BMTB) or extramedullary infiltration by blasts. The blasts are usually of myeloid phenotype (70%), and less commonly of B-lymphoid phenotype (30%). Morphologically and immunophenotypically, myeloid-BC can be of various forms and the differentiation in the blast component can be neutrophilic, eosinophilic, basophilic, monocytic, megakaryocytic or erythroid. Presence of myeloid and lymphoid lineage blasts simultaneously is also known and rare cases of T-lymphoid-BC and promyelocytic-BC have been reported [Alistair G. Reid et al, 2009]. Typical symptoms are due to increasing anemia, thrombocytopenia, basophilia, a rapidly enlarging spleen, and failure of the usual medications to control leukocytosis and splenomegaly. [Maurie Markman, 2009].

In many patients, an accelerated phase occurs 3-6 months before the diagnosis of blast crisis. Clinical features in this phase are intermediate between the chronic phase and blast crisis [Maurie Markman, 2009].

Nonspecific symptoms of tiredness, fatigue, and weight loss may occur long after the onset of the disease. Loss of energy and decreased exercise tolerance may occur during the chronic phase after several months.[Emmanuel CB & Ulrich JW, 2010]

Huge splenomegaly may cause early satiety hence reducing the food intake. Spleen may get infracted and give rise to a "gripping" pain at left upper abdominal quadrant.

Some patients may have low-grade fever and excessive sweating related to hypermetabolism.[Emmanuel CB & Ulrich JW, 2010]

Eye examination should be performed as a routine evaluation in patient diagnosed with leukemia. According to the local study by S.C Reddy et al, 2003 It is most commonly found in association with adult and myeloid leukemia. The common ocular lesions include retinal vascular changes, infiltration of ocular tissue and neuro-ophthalmic sign. Patient may also presented with more than one ocular lesion in either unilateral or bilateral eye.

CML is usually first suspected from routine peripheral blood tests/screenings. [NCCN CPG, 2009] The high white cell count with shift to the left.[Tan KH & Tan SK, 1968] and mild to moderate normochromic and normocytic anemia is a common finding at diagnosis. Platelet count may be low, normal or elevated. Peripheral blood film revealed a hyperleucocytosis with predominance of myelocytes and metamyelocytes. In CML, the leucocyte alkaline phosphatase is low.[Tan KH & Tan SK, 1968]

Bone marrow aspiration may show hypercellularity with expansion of myeloid cell lineage and its progenitor cells. Megakaryocytes are prominent and may be elevated. With reticulin stain, fibrosis can be seen.

Cytogenetic analysis of bone marrow cells cultured by using standard cytogenetic studies (karyotyping) usually disclose the Philadelphia chromosomes which occurs in approximately 95% of patient at diagnosis of CML. [MK Zahry & Ravindran A, 2008]

The remaining 5% might be either being masked (submicroscopic BCR/ABL fusion) or part of a complex / variant chromosome translocation (involving other chromosome breakpoints in addition to 9q34 and 22 q11.) [MK Zahry & Ravindran A, 2008] These latter “Philadelphia chromosome negative” and variant Philadelphia chromosome positive cases can readily be identified by molecular techniques like fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR). [MK Zahry & Ravindran A, 2008]

Bone marrow aspirate and peripheral blood film are both suitable for detecting presence or absence of BCR-ABL transcripts by using RT-PCR. Presence of BCR- ABL is always associated with CML and distinguishing it from other type of leukemia. Therefore it reduces the need for bone marrow aspiration. However, bone marrow aspiration is still the best choice as it may provide baseline functioning of the marrow. One Step Multiplex RT-PCR has been successfully developed to detect BCR-ABL fusion gene. It is a fast and effective technique. The results were comparable with previously reported studies. It should be done routinely in all patients with ALL and CML, as its presence is useful in the management of patients [Rosline H et al, 2005]

Other laboratory abnormalities include hyperuricemia, which is a reflection of high bone marrow cellular turnover and markedly elevated serum vitamin B-12 – binding protein (TC-I). The latter is synthesized by the granulocytes and reflects the degree of leukocytosis.[Emmanuel CB & Ulrich JW, 2010]

Imaging study is un-necessary as the typical hepatosplenomegally are so obvious. Histologically, CML can be classified into CML granulocytic (CMLG) and CML granulocytic-megakaryocytic (CML-GM) based on classification system by Bartl et al. Histological evaluation is a useful investigation in patients of CML at diagnosis as it provides prognostic information. CML- G carry bad prognosis as compared to CML-GM as it can go to blast crisis in a short duration while CML-GM usually remained stable.

The goals of treatment for CML are to achieve hematologic remission, achieve cytogenetic remission and to achieve molecular remission. Apart from that, treatment are attempted to cure the disease, improve patient's quality of life and prolongation of patient survival.

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes are not well described [John M. Goldman, et al, 2010]. The first clinical trial in HCT in human was done by ED Thomas and his colleague in the early 70 while the first autologous BMT was performed by NC Gorin in the mid seventies. John M. Goldman in his article, made a conclusion that recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years have favorable subsequent long-term survival, and their mortality rates eventually approach those of the general population. Daud SS et al in their paper stress on the importance of monitoring chimerism following allogeneic transplantation is that it may enable prompt therapeutic intervention to treat early relapse or rejection; leading to improved outcome. Allogeneic HSCT is a consideration for patients with disease progression on imatinib and for patients presenting with accelerated phase or blast crisis CML [NCCN CPG, 2009]

In Malaysia, the first BMT was performed in University of Malaya in a child in 1987 and in an adult in 1993. [S A W Fadilah et al, 2008] Until 2008, 1,382 patients were transplanted nationwide and registered with the Malaysian Blood and Marrow Transplant Registry with cumulative results that are as good as any well known centers in the West. The numbers of patients treated with HSCT continue to rise over the past 20 years except in patients with chronic myeloid leukemia where the indication of HSCT has declined after 2006 due to the introduction of imatinib mesylate. [S A W Fadilah et al, 2008]

Imatinib mesylate (IM) inhibits the BCR-ABL tyrosine kinase and induces impressive response rates [Sami Joha et al, 2010]. Imatinib Mesylate 400 mg given orally is the standard of care as initial therapy for patients with CML-CP [NCCN CPG, 2009] Imatinib dose escalation from 400 mg to 600 mg or 800 mg as an appropriate initial option for patients with chronic phase (CML-CP) who were experiencing failure or suboptimal cytogenetic response or resistance.[NCCN CPG, 2009]. P C Bee et al, 2006 concluded that local CML patient did well on treatment with imatinib with overall survival was 87%. CML in chronic phase seems to have a better response to imatinib as compared to accelerated and blast crisis. After starting the medication, majority of patient will develop anemia, neutropenia or thrombocytopenia. Others may develop peripheral edema, musculoskeletal pain, gastrointestinal side effect like; nausea, vomiting and diarrhea, grade 1 hepatotoxicity, skin rashes and abnormal renal function test. Anemia commonly occurs in patient with weight less than 60 kg and it is being considered as negative predictors for cytogenetic response. High white blood cell count and absence of cytogenetic response indicate poor survival of the patient. Apart from that, resistance may occur, especially in acute phase of CML [Sami Joha et al, 2010] Resistance can be due to various mechanisms, including BCR-ABL over expression, BCR-ABL point mutations and increased activity of drug efflux transporters[Sami Joha et al, 2010]

Dasatinib was the second BCR-ABL TKI approved for use in patients with Ph-positive chronic phase, accelerated phase, or blast phase CML who are resistant to or intolerant of imatinib. [Maurie Markman, 2009] Nilotinib, the third BCR-ABL TKI is approved for use in patients with Ph-positive chronic phase or accelerated phase CML who are resistant to or intolerant of imatinib.[Maurie Markman, 2009]

Hydroxyurea (Hydrea), an inhibitor of deoxynucleotide synthesis, is the most common myelosuppressive agent used to achieve hematologic remission. .[Emmanuel CB & Ulrich JW, 2010] Baseline blood cell count should be obtained before treatment and its level should be monitor every 2-4 week. Dosage adjustments are depending on the white blood cell level. Most patients achieve hematologic remission within 1-2 months. However, this medication cause only a short duration of myelosuppression and even though peripheral WBC count is low, cytogenic and molecular remission is rare.

Others therapy for CML includes the usage of bisulfan, an alkylating agent which traditionally use to keep the WBC counts less than 15,000 cells/µL. delayed myelosuppressive effect and prolong action making it is difficult to maintain the number within the normal limit. Furthermore, prolong usage of this drug may cause pulmonary fibrosis, hyperpigmentation and sustained marrow suppression for months.

Leukapheresis using a cell separator can lower WBC counts rapidly and safely in patients with WBC counts greater than 300,000 cells/µL, and it can alleviate acute symptoms of leukostasis, hyperviscosity, and tissue infiltration. [Emmanuel CB & Ulrich JW, 2010] Interferon alfa was the treatment of choice for most patients with CML who are too old for bone marrow transplantation (BMT) or who do not have a matched bone marrow donor. Interferon alfa is given at an average of 3-5 million IU/d subcutaneously after hematologic remission with Hydroxyurea. [Emmanuel CB & Ulrich JW, 2010]

Adequate nutrition is an important concern in children with leukemia because malnutrition and weight loss are common and are due to a variety of mechanisms involving the tumour, the host response to the tumour such as infection and phamarcokinetics of chemotherapeutic drugs [Zalina AZ et al, 2009]. The incidence of malnutrition at the time of diagnosis of cancer in children appears to be less than in adults. Some children were malnourished at the time of diagnosis and their malnourishment was reported to have increased during the therapy for malignancy, especially if their treatment involved intensive chemotherapy or bone marrow transplantation. [Zalina AZ et al, 2009] The nutritional status of children with leukemia should be monitored periodically as malnourished children are more prone to infections and complications during treatment and their nutritional status may deteriorate, compared to leukemia children with normal nutritional status.[Zalina AZ et al, 2009]

Response to therapy is usually monitored by the following three parameters: Hematologic response (HR), Cytogenetic response (CR), and Molecular response (MR). Complete hematologic response (CHR) is defined as the normalization of blood counts and spleen size. Cytogenetic response is quantified and graded based upon the percentage of residual Ph’ cells in the bone marrow, as determined by conventional cytogenetic analysis. Currently cytogenetic testing is recommended at the time of establishing the diagnosis and then every six months until complete cytogenetic response (CCR) is achieved. It has been recommended to evaluate subsequently for the potential emergence of cytogenetically abnormal Ph clones. [MK Zahry & Ravindran A, 2008]

The diagnosis of childhood cancer is associated with a great deal of practical and emotional stress for families. All worry, realistically, that the child may die. They must care for the sick child and keep hospital appointments while they continue working and caring for other members of the family. Those living in difficult circumstances are likely to carry a heavier burden, especially where there are few appropriate resources and services. Caring for a sick child almost always falls more heavily on mothers, but in developing countries it is worse.[UICC,2006]

On diagnosis, children are inevitably frightened, traumatized and in pain, but they have different ways of showing their distress. While some become aggressive and hostile towards their carers, others withdraw into themselves. Their quality of life is greatly compromised, compared with that of other children of the same age. They may be unable to go to school or take part in social activities. [UICC,2006]

Young children are upset by visits to hospital, needles, and all the strange people that they have to deal with. They may become “clingy” and insecure and reluctant to leave their parents. Often they act as if they were much younger. They may be afraid to sleep alone and less willing to do things for themselves. Older children may become quite withdrawn but are better able to understand. It is possible to explain what is happening to them and prepare them for some of the procedures. The disadvantage is that this greater understanding may lead to more worries about the potential implications of the disease. They may know they are very ill. They may be afraid they may die but be scared to ask their parents. [UICC,2006]

While on chemotherapy, children may suffer dramatic mood swings and feel very tired and sick [UICC,2006] Mothers tend to shoulder more of the burden of care and report greater emotional distress than fathers. Post-traumatic stress symptoms (PTSS) are common among mothers and fathers, especially following diagnosis [UICC, 2006]

Brothers and sisters are affected too. In all societies, older siblings often play a crucial role in educating and socialising younger children and these, in turn, learn a lot from older siblings. When one child becomes seriously ill, healthy siblings are sad, frightened and concerned about their own health and vulnerability. Older siblings are especially likely to assume responsibility for looking after younger children and helping with domestic tasks. Many develop behavioural and emotional problems at home and school. Others become more mature, compassionate, and independent. [UICC,2006]

Cancer treatment is expensive, and competing priorities for treatment of other conditions must be acknowledged. In the developing world, children often get some treatment for their cancer, but not a curative dose. [UICC,2006] Loss of family income is a problem for all families [UICC,2006]

Overall prognosis for patient with CML is from edian survival of 3 years and a 5-year survival rate of less than 20% to a median survival of 5 or more years and a 5-year survival rate of 50-60% [Emmanuel CB & Ulrich JW, 2010] Poor prognosis is associated with several clinical and laboratory factors, including older age, symptomatic presentation, poor performance status, African American descent, hepatomegaly, splenomegaly, negative Ph chromosome or BCR/ABL, anemia, thrombocytopenia, thrombocytosis, decreased megakaryocytes, basophilia, or myelofibrosis (increased reticulin or collagen). [Emmanuel CB & Ulrich JW, 2010] poor prognosis in relation to therapy includes longer time to hematologic remission with myelosuppression therapy, short duration of remission, total dose of hydroxyurea or busulfan, or poor suppression of Ph-positive cells by chemotherapy or interferon alfa therapy. [Emmanuel CB & Ulrich JW, 2010].


1) Alistair G. Reid, Valeria A. De Melo, Kay Elderfield et al, "Phenotype of blasts in chronic myeloid leukemia in blastic phase—Analysis of bone marrow trephine biopsies and correlation with cytogenetics", Leukemia Research 33 (2009) 418–425, Elsevier

2) A.V. Hoffbrand, P.A.H Moss & J.E. Pettit, " Essential Haematology, 5th edition", Blackwell Publishing, 2006

3) Bina Sharine Menon, Eni Juraida, Hishamshah Ibrahim, et al, "Audit Of Pediatric Hematology-Oncology Outpatients In Kuala Lumpur", Southeast Asian J Trop Med Public Health, Vol 39 No. 4 July 2008

4) Childhood Cancer: Rising to the challenge, International Union Against Cancer (UICC), 2006.

5) Chin Yuet Meng, "PhD Thesis: Cytogenetics and Molecular Studies in Chronic Myeloid Leukemia",2001

6) Daud SS, Ibrahim K & Ariffin H, "Quantitative Evaluation Of Chimerism Status Following Haematopoeitic Stem Cell Transplantation Using A Microchip Electrophoresis System", JUMMEC 2007: 10(1).

7) Emmanuel C Besa & Ulrich Josef Woermann, "Chronic Myelogenous Leukemia", eMedicine, http://emedicine.medscape.com/article/199425

8) John M.G, Navneet S.M, John P.K et al, "Relapse and Late Mortality in 5-Year Survivors of Myeloablative Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia in First Chronic u Phase", JCO April 10, 2010 vol. 28 no. 11 1888-1895

9) Malaysia Clinical Practice Guidelines on Diagnosis and Management Chronic Myeloproliferative Disorders, 2006

10) Malaysian Cancer Statistics - Data And Figure Peninsular Malaysia 2006, National Cancer Registry, Ministry of Health Malaysia, 2006

11) Maurie Markman, "Chronic Myeloid Leukemia and BCR-ABL", eMedicine, http://emedicine.medscape.com/article/1723784

12) Mohd Khairi Zahry & Ravindran Ankathil, "Cytogenetics And Molecular Genetic Tests For The Diagnosis And Treatment Of Chronic Myeloid Leukemia", Bulletin of the Genetics Society of Malaysia, vol 14, No 1, June 2008

13) NCCN Clinical Practice Guidelines in OncologyTM - Asia Consensus Statement: Chronic Myelogenous Leukemia.

14) P C Bee, G G Gan, A Teh & A R Haris, "Imatinib Mesylate In the Treatment of Chronic Myeloid Leukemia : A Local Experience", Med J Malaysia, Vol 61 No 5 December 2006

15) Rosline H, Majdan R, Wan Zaidah et al, "One Step Multiplex Rt-Pcr For Bcr-abl Gene In Malay Patients Diagnosed As Leukaemia", 2005

16) Sami Joha, Véronique Dauphina, Frédéric Leprêtreb et al, "Genomic characterization of Imatinib resistance in CD34+ cell populations from chronic myeloid leukaemia patients", Leukemia Research, 2010

17) S A W Fadilah, C F Leong & S K Cheong, "Stem Cell Transplantation In Malaysia And Future Directions", Med J Malaysia, Vol 63 No 4 October 2008.

18) S.C. Reddy, N. Jackso & B.S. Menon, "Ocular Involvement in Leukemia – A Study of 288 Cases", Ophthalmologica, 2003; 217:441-445.

19) Tan Kwang Hoh & Tan Sim Keng, "Chronic Myeloid Leukaemia in Children", Singapore Medical Journal Vol 9, No 1, 1968

20) WHO, “Cancer", http://www.who.int/topics/cancer/en/

21) WHO, "Cancer Fact Sheet", http://www.who.int/mediacentre/factsheets/fs297/en/index.html

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23) Zalina AZ, Suzana Shahar, A Rahman A Jamal & Noor Aini MY, "Assessing the Nutritional Status of Children with Leukemia from Hospitals in Kuala Lumpur", Mal J Nutr 15(1): 45-51,2009


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