Jump 1: Clarification of Terms Chronic myelogenous leukemia (CML) is a myeloproliferative disorder which involves the hematopoietic stem cell

and is characterized by predominance of maturing myeloid cells in the blood, bone marrow, liver, spleen and other organs. A hematology clinic provides comprehensive consultation and treatment for patients with hematologic disorders. These include anemia, cancers such as leukemia or myeloma, bleeding conditions or problems with excessive blood clotting. Jump 2: Definition of Problem 1. 2. 3. 4. Which treatment options are available? Which treatment is likely to be the best choice for this patient? What are the risk factors of CML? Is there sufficient patient data in the case?

Jump 3: Analyze the Problem 1. Choosing the treatment option for this patient is also difficult since her current state is not clearly stated. Various treatment options may include palliative therapy with hydroxycarbamide, interferon- , combination of interferon- and cytosine, allogenic matched sibling transplant, or most close HLA matched if matched sibling not available, and treatment as part of clinical trial. 2. In choosing the appropriate treatment option, the physician should weigh the risks and benefits of each regimen. The age of the patient should also be considered. 3. Taking into consideration, the risk factors may help the physician to arrive at an accurate diagnosis. 4. The patient's data is unavailable in which the patient's current state is not clear whether in what phase of CML she is having currently. The patient's symptoms are also not known therefore, we do not know what to address. Jump 4: Summary CML is a myeloproliferative disorder characterized by predominance of maturing myeloid cells in various organs. Unfortunately, patients data is insufficient and judging which best treatment option to use is still in question. However, treatment option include hydroxycarbamide, interferon- , cytosine and interferon- , allogenic transplant, and clinical trials involvement. In choosing appropriate treatment option, age is considered and, risks and benefits must be properly weighed. Risk factors of CML may help the physician to arrive at a correct diagnosis. Jump 5: Jump 5: Learning Issues 1. Enumerate the risk factors in the development of CML. 2. Discuss the pathology of CML including their stages. 3. Enumerate the prognostic factors of CML.

4. Discuss the treatment protocols of CML and how to monitor the treatment and response. 5. Discuss the benefits vs risks of the treatment. Jump 7: Reporting and Discussion 1. Risk factors: Age: The average age of a person with CML is around 66. CML is uncommon in children and adolescents. Radiation exposure. There was an increase in the rate of CML seen in Japan in longterm survivors of the atomic bombings. However, there is no proven link in the occurrence of CML following radiation therapy or chemotherapy given for other types of cancer or other diseases. Gender. Men have a slightly higher risk of CML than women. Family history is not a risk factor since the chromosome mutation that leads to CML isn't passed from parents to offspring. This mutation is believed to be acquired (develops after birth). 2. CML was the first malignancy to be linked to a clear genetic abnormality, the chromosomal translocation, Philadelphia chromosome. Part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL (V-abl Abelson murine leukemia viral oncogene) gene on chromosome 9. This abnormal "fusion" genes product is a tyrosine kinase. The fused BCR-ABL protein interacts with the interleukin 3beta(c) receptor subunit. The BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, BCR-ABL activates a cascade of proteins which control the cell cycle, speeding up cell division. Moreover, it inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities.

In staging, the typical clinical course is triphasic:

Phase Chronic phase

Description by Annals of Onclogy None

Accelerated phase (AP)

15%29% blasts are found in blood or bone marrow, >20% basophils in blood, thrombocytosis, thrombocytopenia unrelated to therapy or clonal chromosome abnormalities in the Ph+ clone (CCA/Ph+). Blastic phase characterized by 30% blasts in In blastic phase, 20% or more (BP) or blast blood or bone marrow or are present. When tiredness, crisis (BC) extramedullary blastic infiltration. fever, and enlargement of spleen occur during this phase, it is called blast crisis. 3. Prognostic Factors: A. B. C. D. E. Age Phase Amount of blasts in blood or bone marrow Size of spleen at diagnosis General health

Description by National Cancer Institute of NIH Fewer than 10% of the cells in the blood and bone marrow are blast cells. 10% to 19% is found in accelerated phase in the blood and bone marrow are blast cells.

4. Treatment recommendations for CML based on phase A. Chronic phase Dasatinib 100 mg PO once daily or Nilotinib 300 mg PO twice daily or Imatinib 400 mg PO once daily B. Accelerated/blast phase Dasatinib 140 mg once daily or Nilotinib 400 mg twice daily or Imatinib 600-800 mg PO once daily There is a high relapse rate in patients in accelerated phase even after successful treatment; transplantation should be be considered C. Blast phase: Patients in the blast phase tend to be relatively resistant to most forms of treatment, and there is a high relapse rate in patients in blast crisis even after successful treatment; transplantation should be considered in these patients Patients in lymphoid blast phase can be treated with ALL induction chemotherapy regimens in combination with a tyrosine kinase inhibitor Patients in myeloid blast crisis can be treated with acute myeloid leukemia (AML) induction chemotherapy regimens in combination with a tyrosine kinase inhibitor; some patients can be treated with a tyrosine kinase inhibitor alone

Allogeneic Bone Marrow Transplant Performed after chemotherapy because high-dose chemotherapy destroys both normal and leukemic cells. The International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation have recently reported survival rates of 50 to 60 percent among patients with CML in chronic phase who received chemotherapy alone or radiotherapy plus chemotherapy followed by transplantation of marrow cells from HLA-matched sibling donors. Disadvantage: Graft-versus-host disease - Allograft is curative but it is associated with substantial mortality and potential disabling morbidity for those who survived for a long period of time

Interferon alfa First-line therapy for those who are not eligible for allograft. Combination therapy with cytarabine Disadvantage: Cytarabine: GI and haematological toxicity - addition of PEG-interferon (PEG-IFN) as an alternative to IFN and those who do not respond to imatinib Monitoring of treatment: 1. Measuring the BCR-ABL transcript levels

BCR-ABL transcript levels must be measured every 3mo. If BCR-ABL transcripts are rising (1 log increase from baseline), evaluate patient compliance; if levels are rising (1 log increase) with a major molecular response, repeat evaluation in 1-3mo; if levels are rising (1 log increase) without major molecular response, perform bone marrow cytogenetic analysis; consider mutation testing. 2. FISH Testing Fluorescent in-situ hybridization (FISH) test is a type of cytogenetic test performed on blood cells or marrow cells. It can detect as few as one abnormal cell in 500. Several hundred cells are tagged with a chemical that can make certain genes visible under a special light. The presence or absence of the BCR-ABL gene can be determined. 3. PCR Testing Polymerase chain reaction or PCR is the most sensitive test for monitoring disease progress in CML treatment. Gene amplification is done to look directly at the genetic makeup of blood cells. It is more sensitive than FISH testing because it can find one cell containing Philadelphia chromosome in a million healthy cells. It is recommended that the same laboratory should be used for PCR testing because results may vary from laboratory to laboratory. It is also advisable to use the quantitative PCR in which percentages of leukemic cells are given instead of qualitative PCR which only gives positive or negative as a result. Criteria for responses A. Hematologic response 1. Complete hematologic response complete normalization of peripheral blood counts with a leukocyte count < 10 109/L, a platelet count < 450 109/L no immature cells (eg, myelocytes, promyelocytes, or blasts) in the peripheral blood, no signs and symptoms of disease with disappearance of palpable splenomegaly 2. Partial hematologic response are the same as for a complete hematologic response, except for the presence of immature cells, a platelet count < 50% of the pretreatment count but > 450 109/L, and splenomegaly < 50% of the pretreatment extent B. Cytogenic response bone marrow cytogenetic analysis should be done at 6 and 12mo after initial therapy 1. complete cytogenetic response requires that there be no Ph-positive metaphases if a complete cytogenetic response is achieved at 6mo, it is not necessary to repeat the study at 1y 2. partial cytogenetic response includes 1-35% Ph-positive metaphases C. Molecular response 1. complete molecular response requires that BCR-ABL mRNA be undetectable by reverse transcriptase polymerase chain reaction (RT-PCR) 2. major molecular response includes 3 log reduction of BCR-ABL mRNA

sources www.heathology.com http://carcino.com.msu.edu www.cancer.gov http://emedicine.medscape.com