Philadelphia Positive
Chronic Myeloid Leukemia

Diagnosis, treatment and patient care

Posted by Amaranth Singh, MD on January 17, 2021

Important note: This case study was prepared by FinQuiz for candidates of professional exams.

A 40-year-old woman, otherwise healthy, with no known co-morbid like hypertension and diabetes. There was no history of substance abuse including alcohol or tobacco smoking, presented with a history of left upper quadrant abdominal pain for 12 days which was vague in nature.

LUQ pain wasn’t having any aggravating and relieving factors and was associated with mild swelling of the area. With that, she has progressive weight loss, fatigue, and lethargy correlated with decreased appetite within the duration of 3 months. She denies any recall of TB contact.

She further complains of joint pain and stiffness from the past 1
month. Despite all this, she didn’t have any complaints like fever, cough, sputum production, Shortness of breath (dyspnea), bleeding in the sputum (hemoptysis), chest pain, or PND (proximal nocturnal dyspnea). 

There was no complaint of any bleeding signs or any other related and associated symptoms.


Decrease appetite = 3 months
Progressive weight loss = 3 months
Weakness, lethargy = 3 months
Joint pain and stiffness = 1 months
Left UQ abdominal pain and
swelling = 12 days


On examination, the patient was of average height and underweight.
She was conscious and oriented with GCS=15/15
Blood pressure was 130/80 mm Hg
Pulse rate was regular, at 82/min. 
She was afebrile. 
The respiratory rate was 18/min.
General examination revealed pallor, but no Jaundice, clubbing, cyanosis, or dehydration. There was mild pedal edema present.
Abdominal examination shows mild distention, on palpation, there was moderate hepato-splenomegaly found. 
The rest of the systematic examination including the respiratory system, CNS, and CVS was unremarkable.


Complete Blood Count

Hb: 9.9 g/dL,
total WBC: 66 400/mm3,
differential count: N100 L6,
platelet count: 755000/mm3

Peripheral smear
Normocytic normochromic anemia, leukoerythroblasts, neutrophilia, basophilia, and eosinophilia

Erythrocyte Sedimentation Rate (ESR)
ESR - 25mm/hr

Urea: 12mg/dL
Creatinine: 0.8mg/dL
Potassium: 3.8 mmol/L
Chloride: 98 mmol/L
Bicarb: 26 mmol/L

616.8 IU/L

Uric Acid 
9mg/dL (2.4-6.0 mg/dL)



LAP score: 
50 (control: 324)

USG of Abdomen 
Moderate hepatosplenomegaly.

Bone marrow analysis

Hypercellular marrow with basophilia, eosinophilia, and a mild increase in megakaryocyte number with conglobated and multilobate forms and occasional dwarf forms. <10% blast cells.

Cytogenetic studies of the bone marrow cells 
Philadelphia chromosome, reciprocal translocation of chromosomal material between chromosomes 9 and 22.

Fluorescence in situ hybridization (FISH) 
Positive for BCR-ABL gene


On fluorescence in situ (FISH, the patient was found to have a positive BCR-ABL and Cytogenetic studies of the bone marrow cells = Philadelphia chromosome, reciprocal translocation of chromosomal material between chromosomes 9 and 22 is diagnostic of CML. Reactive causes were very less likely due to extreme leukocytosis, basophilia, peripheral immature cells. Whereas hepato-splenomegaly was evident.


All the symptoms, signs, and lab results point towards a blood disorder. Lets, find out the differential diagnosis.

Polycythemia Vera 
In Polycythemia vera, there must be an increase in RBCs and hematocrit with a lower or no chance of leukocytosis. The Philadelphia chromosome is absent in Polycythemia vera.

Leukemoid reactions 
Like CML, leukemoid reactions will have lower leucocytosis and myeloid bulge. Plus, there will be no basophilia. Enzyme Leukocyte alkaline phosphatase (LAP) is usually high in leukemoid reactions, also Dohle bodies are noted. In CML Leukocyte alkaline phosphatase is lower.

In Normoblastemia, the megakaryocytes and platelets are more frequent and predominant.

Idiopathic myelofibrosis 
IMF is difficult to distinguish from CML. In IMF there will be a lack of basophilia, a lower grade of leukocytosis, and abnormal red cell morphology are more typical of idiopathic myelofibrosis.


Chronic myeloid leukemia (CML) is a disease in which the majority of the patients are asymptomatic, and are discovered incidentally during routine blood testing. Fatigue and loss of energy are the most common symptoms as in this case the patient had anorexia, weight loss, joint pain, and Left Upper Quadrant abdominal pain as well. CML is in general diagnosed through findings such as elevated leukocytosis at complete blood count associated with hepatosplenomegaly at physical examination.

The workup for CML consists of a complete blood picture, a peripheral blood smear, uric acid levels to rule out hyperuricemia, a scan of the abdomen for confirming the hepatosplenomegaly, and bone marrow analysis. 
The confirmation of the diagnosis of CML is based on the presence of the Philadelphia chromosome in bone marrow cells or peripheral blood film. Let’s discuss each of the investigations concerning the symptoms and diagnosis in the above case.

Complete Blood Picture and Peripheral Smear

In CML, the increase in mature neutrophils and total white blood cells. A mild increase in basophils and eosinophils as well. These mature neutrophils, have low vulnerability for apoptosis, resulting in the accumulation of cells that will live longer.

The peripheral blood smear in patients with CML shows the immature white cells and nucleated red cells meaning the leukoerythroblastic pattern, with circulating cells from the bone marrow. 
Early myeloid cells such as nucleated RBCs, myeloblasts, metamyelocytes, and myelocytes will be seen in the peripheral blood smear. The presence of the different progenitor cells differentiates CML from AML.

A moderate to mild anemia is common in patients of CML which is usually normochromic and normocytic. The platelet counts at diagnosis can vary from case to case can be low, or high, and maybe normal too.

In the above case, the patient is anemic, total white cells and platelets are increase. Likewise, peripheral blood film shows Normocytic normochromic anemia, leukoerythroblastic cells, mature neutrophils, basophilia, and eosinophilia.

Bone Marrow Analysis 
In CML bone marrow is hypercellular, with the expansion of the myeloid cells. Megakaryocytes are prominent. Mild fibrosis is often seen. Cytogenetic studies of the bone marrow cells should show a positive Philadelphia chromosome, reciprocal between chromosomes 9 and 22. This is the hallmark of CML.
Moreover, the PCR can detect a positive BCR/ABL (mRNA). Likewise, The new technique of fluorescence in situ hybridization (FISH) uses to detect BCR/ABL (mRNA). 
In the above-discussed case On fluorescence in situ (FISH), the patient was found to have a positive BCR-ABL and Cytogenetic studies of the bone marrow cells = Philadelphia chromosome, reciprocal translocation of chromosomal material between chromosomes 9 and 22 is diagnostic of CML.



Either hydroxyurea or busulfan is equally effective as single medication to provide hematologic control in most of the patients up to 75% or more with CML chronic phase.

The Philadelphia chromosome will also be suppressed with busulfan or hydroxyurea treatment., These chemotherapeutic agents are setting of therapy-induced myelosuppression and are transient. So, let’s put some light on each of three individually.


Hydroxyurea is a ribonucleotide reductase inhibitor. This is a well-tolerated drug and alone effective to control leukocytosis in most of the asymptomatic patients. The monitoring of complete blood counts is regularly required for this treatment.

Initial treatment of CML patients with hydroxyurea starts with 1-4 grams every day. But it’s highly depending on the white cell count, the symptoms, and how urgent it is to lower the white cell count of the individual patient. 
Once the white cell count decreases the dose of hydroxyurea will be individually adjusted with the maintenance of White cell count ranging between 5k-10k/MCL.


Busulfan in chronic phase CML is used on patients who are unable to tolerate or resistant to hydroxyurea. This is an oral alkylating agent. Patients might commonly feel skin hyperpigmentation which resembles Addison’s disease without any alterations in adrenal hormones and weakness as a side effect.

The treatment should be started at a dose of 0.1 mg/kg once a day till white cell count will be reduced by 50%. The white blood count should be monitored every 15 days. Once the white cell count is reduced by 50% the dose of busulfan will be reduced to 0.05 mg/kg once a day. Busulfan is discontinued once the white cell count is less than 20k/ml.


Interferon-alpha is another effective drug of CML. The dose is usually 9 MID/day daily. There are a lot of side effects that can be encountered early in treatment with interferon-alpha, including fever, chills, and anorexia. These are not dose-limiting side effects and usually, decrease after the first few weeks of therapy. 
The patient may be started with hydroxyurea and after achieving the white cell count less than 20k/mcL started with interferon-alpha. 
The dosage of the drug should not be lessened unless the cell count falls below 2k/mcL and/or the platelet count is < 50k/mcL. If this occurs only 25% of dose reduction is recommended. 
Liver enzymes and Renal profile with electrolytes should be repeated every month while on treatment. Likewise, the bone marrow should be repeated every 3rd month, after 6 months of starting the treatment.

Cytosine Arabinoside + Interferon Alpha

Cytosine arabinoside has inside the cell activity against CML. The combination of daily interferon-alpha and cytosine arabinoside was administered as a single subcutaneous dose of 20 mg/m2 /day for 10 days each month than in patients treated with interferon-alpha alone.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation either from bone marrow or peripheral blood is a much effective treatment in CML. Donor transplantation is an effective and potentially curative treatment option for CML. Donors can be related or unrelated but the related and blood relations having the best success rates.

Imatinib Mesylate

Imatinib mesylate is a tyrosine kinase inhibitor. The mechanism of action of imatinib is by inhibiting the abnormal BCR/ABL tyrosine kinase which is created by the positive Philadelphia chromosome translocation abnormality. Imatinib decreases the proliferation and on the other hand, induces apoptosis in cells positive for BCR/ABL.

Dosage of imatinib will be started at 400 mg/day. For achieving the complete up to 98% response rate dose should be increased to 800 mg/day.

If the BCR/ABL gene is overexpressed and ABL genes have mutations patients might show resistance to imatinib. If resistant to imatinib patient can be switched to a different tyrosine kinase inhibitor and should be considered for hematopoietic stem cell transplantation instead.

The renal profile must be monitored while the patient is on imatinib as renal issues are common side effects of imatinib.


•  Awaiting reports of BCR-ABL and because of marked leucocytosis, the patient was started on Hydra (Hydroxyurea) 500mg capsule, (Oral) T.D (twice a day).
•  Day 5 after availability of BCR-ABL, imatinib was added with a dose of 400 mg PO day and may increase to 600 mg/day if tolerated. 
•  Methyl cobalt (Vitamin B-12), 100mcgs injection (Intra-muscular) once a week to overcome anemia due to the loss of appetite.


In our case, the patient responded well to imatinib therapy and the condition stabilized after ten days. At the end of 3 months, hepato-splenomegaly clinically subsided and anemia improved. The patient achieved hemoglobin of 13.8 g/dL, total leucocyte count of 8100/mm3 with normal differential counts, and platelet count of 149 000/mm3. She achieved a complete hematological response after the completion of therapy.


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