Chronic myelogenous leukemia (CML)
From Standard of Care
Pluripotential hematopoietic stem cell malignancy with 3 phases: chronic, followed by accelerated and blast phases.
Classified as a myeloproliferativedisorder.
Chronic phase usually lasts 3 to 5 years.
95% have Philadelphia chromosome t(9;22)(q34;q11).
The cytogenetic abnormality 9;22 chromosomal translocation causes a molecular defect, bcr-abl tyrosine kinase activity responsible for the disease.
Chronic myelogenous leukemia-translocation of chromosomes 9 and 22 leads to the creation of the protein Bcr-Abl, an active cytoplasmic tyrosine kinase implicated in leukemogenesis.
Reciprocal translocation between chromosomes 9 and 22, resulting in fusion of the breakpoint cluster region (BCR) gene on chromosome 22 to the Abelson (ABL) gene on chromosome 9.
The protein product of the BCR-ABL fusion gene is known as p210(BCR-ABL and is a a constitutively active tyrosine kinase enzyme, including the deregulated cellular proliferation that causes the clinical picture of the process.
No known hereditary, familial, geographic or ethnic associations, therefore not an inherited or preventable process.
Increased incidence in persons exposed to the atom bomb in Japan, in radiologists and in patients with ankylosing spondylitis treated with radiation.
The presence of derivative chromosome 9 (der deletions present in 10-15% of patients as identified by FISH techniques and is associated with unfavorable prognosis when treated with hydroxyurea, interferon or bone marrow transplantation.
Younger patients and those with anemia more likely to have 9(der) deletions.
Patients with 9(der) deletions have a higher remission rate with imatinib.
Accounts for 14% of all new leukemiasand 20% of adult leukemias.
Annual incidence of approximately 1 per 100,000 population.
Approximately 4800 new cases in the U.S. in 2008.
Approximately 450 deaths from complications in 2008.
In 2001 there were 23,000 deaths in the U.S. from CML.
Prevalence appears to be increasing.
Median age at presentation is between 50and 60 years and 12-30% of patients at diagnosis are older than 60 years.
Exceedingly rare in childhood.
Approximately 15% enter an accelerated phase.
85% of patients develop acute leukemia.
Majority present in the chronic phase, which may last 4 to 6 years and is often asymptomatic at diagnosis.
Chronic, accelerated and blast crisis phases identified by bone marrow and peripheral blood blasts of less than 15%, greater than 15% but less than 30%, and greater than 30%, respectively.
Accelerated phase may last as long as 1 year.
Acute phase with greater than 30% blasts in the bone marrow or peripheral blood has features of acute leukemia including fever, weight loss, bleeding and anemia.
Acute blastic phase may last 3 to 6 months.
In two thirds of patients in blast crisis the blasts are myeloid and in one third they are lymphoid.
Blast crisis is highly refractory to treatment with response rate to standard induction chemotherapy approximately 20% and the rate of complete remission less than 10%.
Bone marrow transplant is the preferred treatment for younger patients with an HLA-matched sibling donor.
Transplantation of bone marrow from a matched sibling donor or an HLA matched unrelated donor produces equivalent outcomes in patients with chronic myelogenous leukemia, particularly if the transplant takes place within 1 year after diagnosis.
Among patients who undergo transplantation early in the chronic phase of the disease, the survival rate is approximately 70%.
Young patients treated with allogeneic transplant within 1 year of diagnosis have a 10-year survival rate of 50-55%.
10-20% of patients undergoing allogeneic transplant relapse within 3 years.
Lymphocytes from original allogeneic donors infused into relapsed patients can induce complete remission through graft-vs-tumor effect in 60-80% of patients.
In patients with lymphoid blast crisis the response rate to standard chemotherapy is 50% but remissions are short-lived.
Greater than 80% of patients who enter complete cytogenetic response with alpha-interferon are alive for more than 10 years.
Allogeneic stem-cell transplantation during blast crisis has a 5-year survival rate of only 6%.
International Randomized Study of Interferon (IRIS) evaluated interferon plus cytosine arabinoside versus imatinib in 1106 patients with newly diagnosed CML: imatinib complete response 95% vs. interferon alfa and low dose cytosine at 55%, complete cytogenetic response 76% vs. 15% and progression free survival at 18 months 97% vs. 91%, respectively, and the molecular response at 12 months 40% vs., 2%, respectively.
IRIS trial at 6 year analysis: overall survival rate with imatinib was 88%, progression free survival 93% and event free survival rate 83%.
Major molecular response is a more sensitive predictor of long-term progression free survival than complete cytogenetic response and has been established in the IRIS study.
During year 2 of the IRIS study 7.55 of patients on imatinib experienced an event and 2.8% progressed to advanced phase or blast crisis, while the 6 year analysis revealed the event rate dropped to 0.4% and 71% of those who had a complete cytogenetic response, 71% retained that response.
In the IRIS study the cumulative raise cytogenetic response were 69% at one year 87% at 5 years and 89% at 7 years ()'Brien SG, Drucker BJ).
Imatinib has a response rate of 55% in myeloid blast crisis and a complete remission rate of 11%.
Imatinib has a response rate of 70% and a 20% complete remission rate in lymphoid blast crisis.
Imatinib at 400 mg per day 75% of patients enter a complete cytogenetic remission, and with 800 mg/day 90% achieve that type of response.
When resistance to imatinib occurs increasing the dose to 800 mg/day can overcome such resistance but responses are of short duration and tolerability of high dose medication is a problem.
Less than 5% of patients have a polymerase chain reaction (PCR) negative for Bcr/Abl when treated with 400 mg per day of imatinib.
Imatinib the standard of care for front line treatment of chronic phase CML.
International Randomized Study of Interferon and ST1571 trial imatinib as initial treatment 87% achieved complete cytogenetic remission at some time, with progression free survival of 83% and overall survival of 89% at 5 years: 69% of patients remained on the drug.
In the IRIS study most adverse events in the imatinib group we're grade 1-2, with most being superficial edema, nausea, muscle cramps and rashes.
In the IRIS study the most common nonhematologic grade 3-4 adverse events for patients on imatinib or musculoskeletal pain 2.7%, joint pain 2.4% and abdominal pain 2.4%.
In the IRIS study in the hematologic adverse events occurred with neutropenia in 14.3% of patients, thrombocytopenia and 7.8%, and 3.1% developed anemia with imatinib.
Undetectable levels of Bcr/Abl may improve long-term event-free survival.
Risk of developing blast crisis 25% each year.
Three methods used to monitor patients response to treatment include hematologic, cytogenetic and molecular.
The overall relapse rate for newly diagnosed patients with chronic phase of disease treated with imatinib was 16% at a median follow-up of 54 months, but only 7% for those patients with a complete cytogenetic response.
For patients treated with imatinib and in whom the BCR/ABL messenger RNA levels were reduced by at least 3 log the relapse rate was only 3% at 54 months and no patient progressed to accelerated or blast crisis.
Rate of progression of newly diagnosed chronic phase CML patients on imatinib is about 4% per year.
After 60 months of therapy with imatinib complete cytogenetic response was 69% by 12 months and 87% by 60 months.
After 60 months of therapy with imatinib an estimated 7% of patients progressed to accelerated or blast phase.
After 60 months of therapy with imatinib the overall survival was 89%.
97% of patients that demonstrated a complete cytogenetic response within 12 months of thrombocytopenia initiation of imatinib did not progress to accelerated or blast phases by 60 months.
Approximately 30% of patients with chronic phase disease treated with imatinib discontinued therapy after 5 years because of unlsatisfactory therapeutic effects or toxicity.
Mutations including T3151 cause resistance to imatinib and to second line tyrosine kinase inhibitors dasatinib and nilotinib as such agents have difficulty to binding to the T3151 mutation.
Nilotinib use may be superior to imatinib as a first-line therapy for CML, based on the rates of major molecular response and complete cytogenetic response.
In the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENESTnd) 846 patients with newly diagnosed Philadelphia chromosome positive CML were enrolled and randomized to 300 mg of nilotinib twice daily , 400 milligrams twice daily or 400 mg of imatinib once daily: at one year the nilotinib arms were significantly better than the imatinib arm achieving major molecular response (44% vs 22%), and for complete cytogenetic response approximately 79% of patients receiving nilotinib compared with 65% of patients treated with imatinib (Saglio G).
In a study of 519 patients with treatment naïve CML randomized to dasatinib 100 mg once daily or imatinib 400 mg once daily: the median time to major molecular response was faster in the dasatinib arm 6.3 versus 9.2 months for imatinib, a higher major molecular response 45% versus 28%, respectively-suggesting this agent as initial therapy may lead to improved long-term clinical benefits (Kantarjian H et al).
In the above study the overall twelve-month survival was 97.2% for dasatinib and 98.8% for imatinib, complete cytogenetic response rate was twice as high for dasatinib .
Dasatinib induces a complete cytogenetic response in approximately 50% of patients who do not have a response to imatinib or cannot tolerate it (Hochhaus A, Shah NP).
Dasatinib compared to imatinib induced significantly faster and higher rates of complete cytogenetic response and major molecular response given to newly diagnosed patients with chronic CML (Kantarjian H).
In the above study of 519 patients the rate of complete cytogenetic response was 77% for dasatinib and 66% for imatinib, and the rate of major molecular response rate was 46% vs 28%: achieving complete cytogenetic response within 12 months is associated with better long-term progression free survival, dasatinib may improve long-term outcomes among patients with newly diagnosed CML.
BCR-ABL mutations occur in approximately 50% of patients resistant to imatinib.
Up to 20% patients resistant to imatinib have a T3151 mutation.
Omacetaxine can overcome the T1351 mutation.
Most frequent mechanism of resistance to imatinib is the point mutations in the catalytic domain of BCR-ABL.
Mutations account for 36-48% of patients that are not responsive to imatinib, and can occur after treatment