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Chronic myelogenous leukemia (CML) is a slowly progressing disease in which too many white blood cells (not lymphocytes) are made in the bone marrow. Learn about chronic myelogenous leukemia and find information on how we support and care for people with CML before, during, and after treatment.
When looking for the right place to treat your chronic myelogenous leukemia (CML), you want to know you'll be in highly skilled – and truly compassionate — hands. The Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) Adult Leukemia Program includes a team of experienced and caring specialists who aren't just experts in treating cancer; they are world leaders in treating leukemia — and in treating your type of leukemia, in particular.
Exceptional Care for Patients with Chronic Myelogenous Leukemia
World-class care from a full array of specialists — including medical and radiation oncologists, infectious disease specialists, nursing professionals, physician assistants, psychologists, and social workers — with years of expertise in caring for patients with CML.
Development of the personalized treatment plan that's best for you — with options ranging from standard supportive care to intensive chemotherapy, as needed.
Access to both conventional and innovative treatments, including bone marrow/stem cell transplantation, combination chemotherapy, radiation therapy, and immune-based therapies and vaccines.
Close collaboration with you and your family as key members of the treatment team.
Partnership with your referring physician at each stage of your treatment, including follow-up care that's closer to your home.
Comprehensive support services for you and your family, including patient and caregiver education and survivorship programs to help you live well beyond cancer.
The full expertise of two renowned medical centers: Brigham and Women's Hospital and Dana-Farber Cancer Institute.
To schedule a consultation or request a second opinion from our multidisciplinary team, please contact us at 617-632-6028 or 617-632-5138 or fill out our secure online form.
Chronic myelogenous leukemia (also called CML or chronic granulocytic leukemia) is a slowly progressing blood and bone marrow disease that usually occurs during or after middle age, and rarely occurs in children.
Normally, the bone marrow makes bloodstem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell. A lymphoid stem cell becomes a white blood cell.
A myeloid stem cell becomes one of three types of mature blood cells:
In CML, too many blood stem cells become a type of white blood cell called granulocytes. These granulocytes are abnormal and do not become healthy white blood cells. They are also called leukemia cells. The leukemia cells can build up in the blood and bone marrow so there is less room for healthy white blood cells, red blood cells, and platelets. When this happens, infection, anemia, or easy bleeding may occur.
This summary is about chronic myelogenous leukemia. See the following PDQ summaries for more information about leukemia:
These and other signs and symptoms may be caused by CML or by other conditions. Check with your doctor if you have any of the following:
Sometimes CML does not cause any symptoms at all.
Every cell in the body contains DNA (genetic material) that determines how the cell looks and acts. DNA is contained inside chromosomes. In CML, part of the DNA from one chromosome moves to another chromosome. This change is called the “Philadelphia chromosome.” It results in the bone marrow making an enzyme, called tyrosine kinase, that causes too many stem cells to become white blood cells (granulocytes or blasts).
The Philadelphia chromosome is not passed from parent to child.
The following tests and procedures may be used:
One of the following tests may be done on the samples of blood or bone marrow tissue that are removed:
The prognosis (chance of recovery) and treatment options depend on the following:
Staging is the process used to find out how far the cancer has spread. There is no standard staging system for chronic myelogenous leukemia (CML). Instead, the disease is classified by phase: chronic phase, accelerated phase, or blastic phase. It is important to know the phase in order to plan treatment. The information from tests and procedures done to detect (find) and diagnose chronic myelogenous leukemia is also used to plan treatment.
As the amount of blast cells increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may result in infections, anemia, and easy bleeding, as well as bone pain and pain or a feeling of fullness below the ribs on the left side. The number of blast cells in the blood and bone marrow and the severity of signs or symptoms determine the phase of the disease.
In chronic phase CML, fewer than 10% of the cells in the blood and bone marrow are blast cells.
In accelerated phase CML, 10% to 19% of the cells in the blood and bone marrow are blast cells.
In blastic phase CML, 20% or more of the cells in the blood or bone marrow are blast cells. When tiredness, fever, and an enlarged spleen occur during the blastic phase, it is called blast crisis.
In relapsedCML, the number of blast cells increases after a remission.
Different types of treatment are available for patients with chronic myelogenous leukemia (CML). Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information about new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Tyrosine kinase inhibitors are targeted therapy drugs used to treat chronic myelogenous leukemia.
Imatinib mesylate, nilotinib, and dasatinib are tyrosine kinase inhibitors that may be used as initial treatment for newly diagnosed patients with chronic phase CML.
See Drugs Approved for Chronic Myelogenous Leukemia for more information.
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.
Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.
High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.
Stem Cell Transplant
Stem cell transplant (Step 1). Blood is taken from a vein in the arm of the donor. The patient or another person may be the donor. The blood flows through a machine that removes the stem cells. Then the blood is returned to the donor through a vein in the other arm.
Stem cell transplant (Step 2). The patient receives chemotherapy to kill blood-forming cells. The patient may receive radiation therapy (not shown).
Stem cell transplant (Step 3). The patient receives stem cells through a catheter placed into a blood vessel in the chest.
Donor lymphocyte infusion (DLI) is a cancer treatment that may be used after stem cell transplant. Lymphocytes (a type of white blood cell) from the stem cell transplant donor are removed from the donor’s blood and may be frozen for storage. The donor’s lymphocytes are thawed if they were frozen and then given to the patient through one or more infusions. The lymphocytes see the patient’s cancer cells as not belonging to the body and attack them.
Splenectomy is surgery to remove the spleen.
Information about clinical trials is available from the NCI Web site.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.
Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.
Treatment of chronic phase chronic myelogenous leukemia may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with chronic phase chronic myelogenous leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of accelerated phase chronic myelogenous leukemia may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with accelerated phase chronic myelogenous leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of blastic phase chronic myelogenous leukemia may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with blastic phase chronic myelogenous leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Treatment of relapsedchronic myelogenous leukemia may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with relapsing chronic myelogenous leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
For more information from the National Cancer Institute about chronic myelogenous leukemia, see the following:
For general cancer information and other resources from the National Cancer Institute, see the following:
This information is provided by the National Cancer Institute.
This information was last updated on June 27, 2014.
Estimated new cases and deaths from CML in the United States in 2014:
CML is one of a group of diseases called the
myeloproliferative disorders. Other related entities include the following:
(Refer to the PDQ summary on Chronic Myeloproliferative Neoplasms Treatment for more information.)
CML is a clonal disorder that is usually easily diagnosed
because the leukemic cells of more than 95% of patients have a distinctive
cytogenetic abnormality, the Philadelphia chromosome (Ph1). The Ph1
results from a reciprocal translocation between the long arms of
chromosomes 9 and 22 and is demonstrable in all hematopoietic precursors.
This translocation results in the transfer of the Abelson (ABL) on chromosome 9 oncogene to an
area of chromosome 22 termed the breakpoint cluster region (BCR). This, in
turn, results in a fused BCR/ABL gene and in the production of an abnormal
tyrosine kinase protein that causes the disordered myelopoiesis found in CML.
Furthermore, these molecular techniques can now be used to supplement
cytogenetic studies to detect the presence of the 9;22 translocation in
patients without a visible Ph1 (Ph1-negative).
Ph1-negative CML is a poorly defined
entity that is less clearly distinguished from other myeloproliferative
syndromes. Patients with Ph1-negative CML generally have a poorer response to treatment
and shorter survival than Ph1-positive patients. Ph1-negative patients who have BCR/ABL gene rearrangement detectable by Southern blot analysis, however, have prognoses
equivalent to Ph1-positive patients.
A small subset of patients have BCR/ABL detectable only by reverse transcriptase–polymerase chain reaction (RT–PCR),
which is the most sensitive technique currently available. Patients with RT–PCR evidence of the BCR/ABL fusion gene appear clinically and prognostically
identical to patients with a classic Ph1; however, patients who are BCR/ABL-negative by RT–PCR have a clinical course more consistent with chronic
myelomonocytic leukemia, which is a distinct clinical entity related to myelodysplastic
syndrome. Fluorescent in situ hybridization of the BCR/ABL translocation can be performed on the bone marrow aspirate or on the peripheral blood of patients with CML.
At the time of diagnosis of patients with CML, splenomegaly is the most common finding on physical examination. The spleen may be enormous, filling most of the abdomen and
presenting a significant clinical problem, or the spleen may be only minimally
enlarged. In about 10% of patients, the spleen is neither palpable nor
enlarged on splenic scan.
The median age of patients with Ph1-positive CML is 67 years. While the median survival used to be 4 to 6 years, with the advent of the new oral therapies, the median survival is expected to approach normal life expectancy for most patients, although it is still too soon to say this definitively.
American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014.
Kurzrock R, Kantarjian HM, Druker BJ, et al.: Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 138 (10): 819-30, 2003.
Goldman JM, Melo JV: Chronic myeloid leukemia--advances in biology and new approaches to treatment. N Engl J Med 349 (15): 1451-64, 2003.
Deininger MW, Goldman JM, Melo JV: The molecular biology of chronic myeloid leukemia. Blood 96 (10): 3343-56, 2000.
Onida F, Ball G, Kantarjian HM, et al.: Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia. Cancer 95 (8): 1673-84, 2002.
Martiat P, Michaux JL, Rodhain J: Philadelphia-negative (Ph-) chronic myeloid leukemia (CML): comparison with Ph+ CML and chronic myelomonocytic leukemia. The Groupe Français de Cytogénétique Hématologique. Blood 78 (1): 205-11, 1991.
Cortes JE, Talpaz M, Beran M, et al.: Philadelphia chromosome-negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Long-term follow-up results. Cancer 75 (2): 464-70, 1995.
Oscier DG: Atypical chronic myeloid leukaemia, a distinct clinical entity related to the myelodysplastic syndrome? Br J Haematol 92 (3): 582-6, 1996.
Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al.: BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol 19 (11): 2915-26, 2001.
Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol 87 (11): 1037-45, 2012.
Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic myelogenous leukemia: playing the odds. J Clin Oncol 16 (9): 2897-903, 1998.
Bone marrow sampling is done to assess cellularity, fibrosis, and cytogenetics.
The Philadelphia chromosome (Ph1) is usually more readily apparent in marrow
metaphases than in peripheral blood metaphases; in some cases, it may be
mashed and reverse transcriptase–polymerase chain reaction (RT–PCR) or fluorescent in situ hybridization analyses on blood or marrow aspirates may be necessary to demonstrate the 9;22
Histopathologic examination of bone marrow aspirate demonstrates a shift in the
myeloid series to immature forms that increase in number as patients progress
to the blastic phase of the disease. The marrow is hypercellular, and
differential counts of both marrow and blood show a spectrum of mature and
immature granulocytes similar to that found in normal marrow. Increased
numbers of eosinophils or basophils are often present, and sometimes
monocytosis is seen. Increased megakaryocytes are often found in the marrow,
and sometimes fragments of megakaryocytic nuclei are present in the blood,
especially when the platelet count is very high. The percentage of lymphocytes
is reduced in both the marrow and blood in comparison with normal subjects, and
the myeloid/erythroid ratio in the marrow is usually greatly elevated. The
leukocyte alkaline phosphatase enzyme is either absent or markedly reduced in
the neutrophils of patients with CML.
Transition from the chronic phase to the accelerated phase and later the blastic
phase may occur gradually over a period of 1 year or more, or it may appear
abruptly (blast crisis). The annual rate of progression from chronic phase
to blast crisis is 5% to 10% in the first 2 years and 20% in subsequent
years. Signs and symptoms commonly indicating such a change include the following:
In the accelerated phase, differentiated cells persist,
though they often show increasing morphologic abnormalities, and increasing
anemia and thrombocytopenia and marrow fibrosis are apparent.
Studies have suggested that certain presenting features have prognostic
The following are predictive of a shorter chronic phase:
Predictive models using multivariate analysis have been derived.
Chronic-phase CML is characterized by bone marrow and cytogenetic findings as described above with
less than 10% blasts and promyelocytes in the peripheral blood and bone marrow.
Accelerated-phase CML is characterized by 10% to 19% blasts in either the peripheral blood or bone
Blastic-phase CML is characterized by 20% or more blasts in the peripheral blood or bone marrow.
When 20% or more blasts are present in the face of fever, malaise, and
progressive splenomegaly, the patient has entered blast crisis.
Relapsed CML is characterized by any evidence of progression of disease from a stable remission. This may include the following:
Detection of the BCR/ABL translocation by RT–PCR during prolonged remissions does not constitute relapse on its own. However, exponential drops in quantitative RT–PCR measurements for 3 to 12 months correlates with the degree of cytogenetic response, just as exponential rises may be associated with quantitative RT–PCR measurements that are closely connected with clinical relapse.
Sokal JE, Cox EB, Baccarani M, et al.: Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 63 (4): 789-99, 1984.
Sokal JE, Baccarani M, Russo D, et al.: Staging and prognosis in chronic myelogenous leukemia. Semin Hematol 25 (1): 49-61, 1988.
Fabarius A, Leitner A, Hochhaus A, et al.: Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 118 (26): 6760-8, 2011.
Kantarjian HM, Smith TL, McCredie KB, et al.: Chronic myelogenous leukemia: a multivariate analysis of the associations of patient characteristics and therapy with survival. Blood 66 (6): 1326-35, 1985.
Sacchi S, Kantarjian HM, Smith TL, et al.: Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia. J Clin Oncol 16 (3): 882-9, 1998.
Hasford J, Pfirrmann M, Hehlmann R, et al.: A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 90 (11): 850-8, 1998.
Kvasnicka HM, Thiele J, Schmitt-Graeff A, et al.: Bone marrow features improve prognostic efficiency in multivariate risk classification of chronic-phase Ph(1+) chronic myelogenous leukemia: a multicenter trial. J Clin Oncol 19 (12): 2994-3009, 2001.
Cortes JE, Talpaz M, O'Brien S, et al.: Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer 106 (6): 1306-15, 2006.
Martinelli G, Iacobucci I, Rosti G, et al.: Prediction of response to imatinib by prospective quantitation of BCR-ABL transcript in late chronic phase chronic myeloid leukemia patients. Ann Oncol 17 (3): 495-502, 2006.
Treatment of patients with chronic myelogenous leukemia (CML) is usually initiated when the
diagnosis is established, which is done by the presence of an elevated white
blood cell (WBC) count, splenomegaly, thrombocytosis, and identification of the BCR/ABL (breakpoint cluster region/Abelson) translocation. The optimal frontline treatment for patients with chronic-phase CML is the subject of active clinical evaluation but involves specific inhibitors of the BCR/ABL tyrosine kinase.
In a randomized trial comparing imatinib mesylate with interferon plus cytarabine, with 5 years' median follow-up, imatinib mesylate induced complete cytogenetic responses in more than 80% of newly diagnosed patients; in addition, the annual rate of progression to accelerated phase or blast crisis dropped from 2% to less than 1% in the fourth year on the imatinib arm.[Level of evidence: 1iiDiii] However, most of these continually responding patients still showed detectable evidence of the BCR/ABL translocation by the most sensitive measurement of reverse transcriptase–polymerase chain reaction (RT–PCR). The clinical implication of this finding after 10 years or more is unknown, but these results have changed clinical practice. Although evidence-based survival advantages are unavailable because of crossover in randomized trials, the overall survival rate for all patients at 5 years is 89%, with fewer than 50% of all deaths (4.5%) caused by CML.
Tyrosine kinase inhibitors with greater potency and selectivity than imatinib for BCR/ABL have been evaluated in newly diagnosed patients with CML. In a randomized, prospective study of 846 patients comparing nilotinib with imatinib, the rate of major molecular response at 24 months was 71% and 67% for two-dose schedules of nilotinib and 44% for imatinib (P < .0001 for both comparisons).[Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in 17 patients on imatinib (14%), but this progression only occurred in two patients (<1%, P = . 0003) and in five patients (<1.8%, P = .0089), respectively, on two-dose schedules of nilotinib.
Similarly, in a randomized, prospective study of 519 patients comparing dasatinib with imatinib, the rate of major molecular response at 12 months was 46% for dasatinib and 28% for imatinib (P < .0001). The rate of major molecular response at 24 months was 64% for dasatinib and 46% for imatinib (P < .0001).[Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in 13 patients (5%) on imatinib and in six patients (2.3%) on dasatinib (not statistically different).
Although one of these two studies showed statistically significant decreased rates of progression to accelerated or blastic phase, which may ultimately translate into improved survival, the follow-up period with nilotinib and dasatinib has not been long enough to detect and confirm this prolonged survival with these agents. The preferred initial treatment for newly diagnosed patients with chronic-phase CML could be any of these specific inhibitors of the BCR/ABL tyrosine kinase.
The only consistently successful curative treatment of CML beyond 10 years' follow-up has been allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT). Long-term data beyond 10 years of therapy are available, and most long-term survivors show no evidence of the BCR/ABL translocation by any available test (e.g., cytogenetics, RT–PCR, or fluorescent in situ hybridization [FISH]). Many patients, however, are not eligible for this approach because of age, comorbid conditions, or lack of a suitable donor. In addition, substantial morbidity and mortality result from allogeneic BMT or SCT; a 15% to 30% treatment-related mortality can be expected, depending on whether a donor is related and on the presence of mismatched antigens.
Long-term data are also available for patients treated with interferon alpha. Approximately 10% to 20% of these patients have a complete cytogenetic response with no evidence of BCR/ABL translocation by any available test, and the majority of these patients are disease free beyond 10 years. Maintenance of therapy with interferon is required, however, and some patients experience side effects that preclude continued treatment.
Newly diagnosed patients with very high levels of circulating leukocytes (WBC >100,000/mm3) require immediate therapy with imatinib mesylate to avoid cerebrovascular events or death from leukostasis. Leukophoresis and plateletpheresis are sometimes required for an even more emergent reduction of counts.
Druker BJ, Guilhot F, O'Brien SG, et al.: Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355 (23): 2408-17, 2006.
Bhatia R, Holtz M, Niu N, et al.: Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 101 (12): 4701-7, 2003.
Hughes TP, Kaeda J, Branford S, et al.: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349 (15): 1423-32, 2003.
Rosti G, Martinelli G, Bassi S, et al.: Molecular response to imatinib in late chronic-phase chronic myeloid leukemia. Blood 103 (6): 2284-90, 2004.
Kantarjian HM, Talpaz M, O'Brien S, et al.: Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 108 (6): 1835-40, 2006.
Kantarjian HM, Hochhaus A, Saglio G, et al.: Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 12 (9): 841-51, 2011.
Kantarjian HM, Shah NP, Cortes JE, et al.: Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 119 (5): 1123-9, 2012.
Wei G, Rafiyath S, Liu D: First-line treatment for chronic myeloid leukemia: dasatinib, nilotinib, or imatinib. J Hematol Oncol 3: 47, 2010.
Ozer H, George SL, Schiffer CA, et al.: Prolonged subcutaneous administration of recombinant alpha 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: effect on remission duration and survival: Cancer and Leukemia Group B study 8583. Blood 82 (10): 2975-84, 1993.
Kantarjian HM, Smith TL, O'Brien S, et al.: Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy. The Leukemia Service. Ann Intern Med 122 (4): 254-61, 1995.
Long-term follow-up of the Italian trial of interferon-alpha versus conventional chemotherapy in chronic myeloid leukemia. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Blood 92 (5): 1541-8, 1998.
A trial randomly assigning 1,106 previously untreated patients to imatinib mesylate or to interferon plus cytarabine documented a 76% complete cytogenetic response rate with imatinib mesylate versus 14% for interferon plus cytarabine at a median follow-up of 19 months.[Level of evidence: 1iiDiii] At 18 months, 96.7% of the imatinib group had avoided progression to accelerated-phase CML or blast crisis compared with 91.5% of the interferon plus cytarabine group (P < .001). Because 90% of the combination group had switched to imatinib by 18 months (mostly because of intolerance of side effects), a survival difference may never be observed. By the 5-year median follow-up of this trial, imatinib mesylate induced complete cytogenetic response in more than 80% of the participants, with the annual rate of progression to accelerated-phase CML or blast crisis dropping from 2% in the first year to less than 1% in the fourth year. In addition, the overall survival (OS) rate for all patients at 5 years is 89%, with fewer than 50% of all deaths (4.5%) caused by CML. More than 90% of completely responding patients still show detectable evidence of the BCR/ABL translocation, usually by reverse transcription-polymerase chain reaction (RT–PCR) or by fluorescence in situ hybridization of progenitor cell cultures. The clinical implication of this finding after 10 years or more is unknown, but these results have changed clinical practice. Poor compliance is the predominant reason for inadequate molecular response to imatinib.
Tyrosine kinase inhibitors with greater potency and selectivity for BCR/ABL than imatinib have been evaluated in newly diagnosed patients with CML. In a randomized, prospective study of 846 patients that compared nilotinib with imatinib, the rate of major molecular response at 24 months was 71% and 67% for two-dose schedules of nilotinib and 44% for imatinib (P < .0001 for both comparisons).[Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in 17 patients on imatinib (14%), but this progression only occurred in two patients (<1%, P = .0003) and in five patients (1.8%, P = .0089), respectively, for those patients on two-dose schedules of nilotinib. Nilotinib-treated patients had a lower rate of treatment-emergent BCR/ABL mutations than did imatinib-treated patients.
Similarly, in a randomized, prospective study of 519 patients that compared dasatinib with imatinib, the rate of major molecular response at 12 months was 46% for dasatinib and 28% for imatinib (P < .0001). The rate of major molecular response at 24 months was 64% for dasatinib and 46% for imatinib (P < .0001).[Level of evidence: 1iiDiv] Progression to accelerated-phase CML or blast crisis occurred in 13 patients (5%) on imatinib and in six patients (2.3%) on dasatinib (not statistically different).
Although one of these two studies showed statistically significant decreased rates of progression to accelerated- or blastic-phase CML, which may ultimately translate into improved survival, the follow-up period with nilotinib and dasatinib has not been long enough to detect and confirm this prolonged survival with these agents. The preferred initial treatment for newly diagnosed patients with chronic-phase CML could be any of these specific inhibitors of the BCR/ABL tyrosine kinase.
Higher doses of imatinib mesylate, alternative tyrosine kinase inhibitors (such as dasatinib or nilotinib, and allogeneic SCT) are implemented for suboptimal response or progression and are under clinical evaluation as frontline approaches. Currently in practice, dose escalation of imatinib is usually the first step taken for suboptimal response, but clinical trials are required to establish the relative efficacy and sequencing of dose escalation, dasatinib, and nilotinib. Two studies looked at dose escalation of imatinib in almost 200 previously untreated patients, most of whom were of intermediate Sokal risk; 63% to 73% achieved a major molecular response by 18 to 24 months and only three patients showed progression to advanced phase in these preliminary phase II results.[Level of evidence: 3iiiDiv] Until randomized studies are performed, it is unclear whether the increased response with increased dosage will translate into longer durations of response or survival advantages.
A single-center, retrospective analysis of 483 patients with chronic phase CML who were treated with imatinib (400 mg or 800 mg daily), dasatinib, or nilotinib, indicated that patients who have better than 35% t(9;22)+ cells at 3 months of therapy have inferior event-free, transformation-free, and OS rates compared with patients who have better early cytogenetic responses.
Among the many unanswered questions are the following:
All of these issues have led to an active reappraisal of recommendations for optimal frontline therapy for chronic-phase CML.
The only consistently successful curative treatment of CML has been high-dose therapy followed by allogeneic BMT or SCT. Patients younger than 60 years with an identical twin or with
HLA-identical siblings can be considered for BMT early in the chronic phase. Although the procedure is associated with
considerable acute morbidity and mortality, 50% to 70%
of patients transplanted in the chronic phase survive 2 to 3 years, and the
results are better in younger patients, especially those younger than 20 years.
The results of patients transplanted in the accelerated and blastic phases of the
disease are progressively worse. Most transplant series suggest improved survival when the
procedure is performed within 1 year of diagnosis.[Level of evidence: 3iiiA] The data supporting early transplant, however, have never been confirmed in controlled
trials. In a randomized, clinical trial, disease-free survival and OS were
comparable when allogeneic transplantation followed preparative therapy with
cyclophosphamide and total-body irradiation (TBI) or busulfan and
cyclophosphamide without TBI. The latter regimen was associated with less
graft-versus-host disease and fewer fevers, hospitalizations, and hospital
days.[Level of evidence: 1iiA] Reduced-intensity conditioning allogeneic SCT is under evaluation in first or second remissions.
About 20% of otherwise eligible CML patients lack a suitably matched sibling
donor. HLA-matched unrelated donors or donors mismatched at one-HLA antigen
can be found for about 50% of eligible participants through the National Marrow
Donor Program. A retrospective review of 2,444 patients who received myeloablative allogeneic SCT showed OS at 15 years of 88% (95% confidence interval [CI], 86%–90%) for sibling-matched transplant and of 87% (95% CI, 83%–90%) for unrelated donor transplant. The cumulative incidences of relapse were 8% (95% CI, 7%–10%) for sibling-matched transplant and 2% (95% CI, 1%– 4%) for unrelated donor transplant.
Although the majority of relapses occur within 5 years
of transplantation, relapses have occurred for as long as 15 years following BMT. In a molecular analysis of 243 patients who underwent allogeneic BMT over a 20-year interval, only 15% had no detectable BCR/ABL transcript by PCR analysis.
The risk of relapse appears to be less in patients transplanted early in
disease and in patients who develop chronic graft-versus-host disease.
With the advent of imatinib, dasatinib, and nilotinib, the timing and sequence of allogeneic BMT or SCT has been cast in doubt. Allogeneic SCT is the preferred choice for patients presenting with accelerated-phase or blast-phase disease, for patients with a T3151 mutation (resistant to currently available tyrosine kinase inhibitors), and for patients with complete intolerance to the pharmacologic options.
In a prospective trial of 354 patients aged younger than 60 years, 123 of 135 patients with a matched, related donor underwent early allogeneic SCT while the others received interferon-based therapy and imatinib at relapse; some also underwent a matched, unrelated-donor transplant in remission. With a 9-year median follow-up, survival still favored the drug treatment arm (P = .049), but most of the benefit was early as a result of transplant-related mortality, with the survival curves converging by 8 years.[Level of evidence: 2A] Among the many unanswered questions are the following:
Clinical trials and long-term results from ongoing trials will be required before these controversies are resolved.
For patients resistant to the tyrosine kinase inhibitor, omacetaxine mepesuccinate (a cephalotaxine, formerly known as homoharringtonine, with activity independent of BCR/ABL) has shown a hematologic response rate of 67% and a median progression-free survival of 7 months in a small, phase II study of 46 patients.[Level of evidence: 3iiiDiv]
Hydroxyurea is given daily by mouth (1–3 g per day as a single dose on
an empty stomach). Hydroxyurea is superior to busulfan in the chronic phase of
CML, with significantly longer median survival and significantly fewer severe
adverse effects. A dose of 40 mg/kg per day is often
used initially and frequently results in a rapid reduction of the white blood
cell (WBC) count. When the WBC count drops below 20,000 mm3,
the hydroxyurea is often reduced and titrated to maintain a WBC count between
5,000 and 20,000. Hydroxyurea is
currently used primarily to stabilize patients with hyperleukocytosis or as
palliative therapy for patients who have not responded to other therapies.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with chronic phase chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
O'Brien SG, Guilhot F, Larson RA, et al.: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348 (11): 994-1004, 2003.
Marin D, Bazeos A, Mahon FX, et al.: Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 28 (14): 2381-8, 2010.
Hochhaus A, Saglio G, Larson RA, et al.: Nilotinib is associated with a reduced incidence of BCR-ABL mutations vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood 121 (18): 3703-8, 2013.
Jabbour E, Cortes J, Kantarjian HM, et al.: Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. Blood 108 (4): 1421-3, 2006.
Cortes JE, Jones D, O'Brien S, et al.: Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol 28 (3): 392-7, 2010.
Apperley JF, Cortes JE, Kim DW, et al.: Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol 27 (21): 3472-9, 2009.
Cortes JE, Jones D, O'Brien S, et al.: Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol 28 (3): 398-404, 2010.
Kantarjian HM, Larson RA, Guilhot F, et al.: Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 115 (3): 551-60, 2009.
Jabbour E, Cortes JE, Kantarjian HM: Suboptimal response to or failure of imatinib treatment for chronic myeloid leukemia: what is the optimal strategy? Mayo Clin Proc 84 (2): 161-9, 2009.
Jabbour E, Kantarjian HM, Jones D, et al.: Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 113 (10): 2154-60, 2009.
Cortes JE, Baccarani M, Guilhot F, et al.: Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol 28 (3): 424-30, 2010.
Rosti G, Palandri F, Castagnetti F, et al.: Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood 114 (24): 4933-8, 2009.
Castagnetti F, Palandri F, Amabile M, et al.: Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party. Blood 113 (15): 3428-34, 2009.
Cortes JE, Kantarjian HM, Goldberg SL, et al.: High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J Clin Oncol 27 (28): 4754-9, 2009.
Hehlmann R, Lauseker M, Jung-Munkwitz S, et al.: Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29 (12): 1634-42, 2011.
Jain P, Kantarjian H, Nazha A, et al.: Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities. Blood 121 (24): 4867-74, 2013.
Mahon FX, Réa D, Guilhot J, et al.: Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11 (11): 1029-35, 2010.
Peggs K, Mackinnon S: Imatinib mesylate--the new gold standard for treatment of chronic myeloid leukemia. N Engl J Med 348 (11): 1048-50, 2003.
Saussele S, Lauseker M, Gratwohl A, et al.: Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood 115 (10): 1880-5, 2010.
Preudhomme C, Guilhot J, Nicolini FE, et al.: Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 363 (26): 2511-21, 2010.
Gratwohl A, Hermans J: Allogeneic bone marrow transplantation for chronic myeloid leukemia. Working Party Chronic Leukemia of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 17 (Suppl 3): S7-9, 1996.
Wagner JE, Zahurak M, Piantadosi S, et al.: Bone marrow transplantation of chronic myelogenous leukemia in chronic phase: evaluation of risks and benefits. J Clin Oncol 10 (5): 779-89, 1992.
Enright H, Davies SM, DeFor T, et al.: Relapse after non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: early transplantation, use of an unrelated donor, and chronic graft-versus-host disease are protective. Blood 88 (2): 714-20, 1996.
Goldman JM, Szydlo R, Horowitz MM, et al.: Choice of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase. Blood 82 (7): 2235-8, 1993.
Clift RA, Appelbaum FR, Thomas ED: Treatment of chronic myeloid leukemia by marrow transplantation. Blood 82 (7): 1954-6, 1993.
Hansen JA, Gooley TA, Martin PJ, et al.: Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 338 (14): 962-8, 1998.
Clift RA, Buckner CD, Thomas ED, et al.: Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood 84 (6): 2036-43, 1994.
Crawley C, Szydlo R, Lalancette M, et al.: Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 106 (9): 2969-76, 2005.
Bacher U, Klyuchnikov E, Zabelina T, et al.: The changing scene of allogeneic stem cell transplantation for chronic myeloid leukemia--a report from the German Registry covering the period from 1998 to 2004. Ann Hematol 88 (12): 1237-47, 2009.
Goldman JM, Majhail NS, Klein JP, et al.: Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase. J Clin Oncol 28 (11): 1888-95, 2010.
Maziarz R: Transplantation for CML: lifelong PCR monitoring? Blood 107 (10): 3820, 2006.
Kaeda J, O'Shea D, Szydlo RM, et al.: Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood 107 (10): 4171-6, 2006.
Pichert G, Roy DC, Gonin R, et al.: Distinct patterns of minimal residual disease associated with graft-versus-host disease after allogeneic bone marrow transplantation for chronic myelogenous leukemia. J Clin Oncol 13 (7): 1704-13, 1995.
O'Brien S, Berman E, Moore JO, et al.: NCCN Task Force report: tyrosine kinase inhibitor therapy selection in the management of patients with chronic myelogenous leukemia. J Natl Compr Canc Netw 9 (Suppl 2): S1-25, 2011.
Hehlmann R, Berger U, Pfirrmann M, et al.: Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood 109 (11): 4686-92, 2007.
Cortes J, Digumarti R, Parikh PM, et al.: Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol 88 (5): 350-4, 2013.
Hehlmann R, Heimpel H, Hasford J, et al.: Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation of survival by hydroxyurea. The German CML Study Group. Blood 82 (2): 398-407, 1993.
Patients with accelerated-phase CML show signs of progression without meeting the criteria for blast crisis (acute leukemia). Symptoms and findings include the following:
Bone marrow examination shows increasing blast cell percentage (but ≤30%) and basophilia. Additional cytogenetic abnormalities occur during the accelerated phase (trisomy 8, trisomy 19, isochromosome 17Q, p53 mutations or deletions), and the combination of hematologic progression plus additional cytogenetic abnormalities predicts for lower response rates and a shorter time-to-treatment failure on imatinib mesylate. At 1 year after the start of imatinib, the failure rate is 68% for patients with both hematologic progression and cytogenetic abnormalities, 31% for patients with only hematologic progression, and 0% for patients with cytogenetic abnormalities only. Before the availability of imatinib, the median survival time of accelerated-phase CML patients was less than 1 year.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with accelerated phase chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Jiang Q, Xu LP, Liu DH, et al.: Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in the accelerated phase. Blood 117 (11): 3032-40, 2011.
Kantarjian H, Talpaz M, O'Brien S, et al.: Survival benefit with imatinib mesylate therapy in patients with accelerated-phase chronic myelogenous leukemia--comparison with historic experience. Cancer 103 (10): 2099-108, 2005.
Cortes J, Talpaz M, O'Brien S, et al.: Suppression of cytogenetic clonal evolution with interferon alfa therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. J Clin Oncol 16 (10): 3279-85, 1998.
Kantarjian HM, Keating MJ, Estey EH, et al.: Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-alpha and low-dose cytarabine. J Clin Oncol 10 (5): 772-8, 1992.
Kantarjian HM, Talpaz M, Kontoyiannis D, et al.: Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor. J Clin Oncol 10 (3): 398-405, 1992.
O'Dwyer ME, Mauro MJ, Kurilik G, et al.: The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood 100 (5): 1628-33, 2002.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with blastic phase chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344 (14): 1038-42, 2001.
Saglio G, Hochhaus A, Goh YT, et al.: Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer 116 (16): 3852-61, 2010.
Kantarjian HM, Cortes J, O'Brien S, et al.: Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood 99 (10): 3547-53, 2002.
Sawyers CL, Hochhaus A, Feldman E, et al.: Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 99 (10): 3530-9, 2002.
Fruehauf S, Topaly J, Buss EC, et al.: Imatinib combined with mitoxantrone/etoposide and cytarabine is an effective induction therapy for patients with chronic myeloid leukemia in myeloid blast crisis. Cancer 109 (8): 1543-9, 2007.
Preti HA, O'Brien S, Giralt S, et al.: Philadelphia-chromosome-positive adult acute lymphocytic leukemia: characteristics, treatment results, and prognosis in 41 patients. Am J Med 97 (1): 60-5, 1994.
Walters RS, Kantarjian HM, Keating MJ, et al.: Therapy of lymphoid and undifferentiated chronic myelogenous leukemia in blast crisis with continuous vincristine and adriamycin infusions plus high-dose decadron. Cancer 60 (8): 1708-12, 1987.
Overt failure is defined as a loss of hematologic remission or progression to accelerated-phase or blast-crisis phase CML as previously defined. A consistently rising quantitative reverse–transcription polymerase chain reaction BCR/ABL level suggests relapsing disease. For initial use of imatinib mesylate, the designation of relative failure or suboptimal response has been proposed for lack of complete hematologic remission by 3 months, no cytogenetic response by 6 months, or no major cytogenetic response by 12 months. Nilotinib and dasatinib induce such high rates of complete cytogenetic responses and major molecular responses within several months that new benchmarks are required for responsiveness. These investigators propose that a complete cytogenetic response by 3 months should define an optimal response.
In case of treatment failure or suboptimal response, patients should undergo BCR/ABL kinase domain mutation analysis to help guide therapy with the newer tyrosine kinase inhibitors or with allogeneic transplantation. Mutations in the tyrosine kinase domain can confer resistance to imatinib mesylate; alternative inhibitors such as dasatinib, nilotinib, or bosutinib, higher doses of imatinib mesylate, and allogeneic stem cell transplantation (SCT) have been studied in this setting. In particular, the T315I mutation marks resistance to imatinib, dasatinib, nilotinib, and bosutinib. In a phase I escalation study with 81 patients, patients with the T315I mutation responded to ponatinib, an oral tyrosine kinase inhibitor.[Level of evidence: 3iiiDiv] Ponatinib also has activity in heavily pretreated-resistant CML and in a third of the patients with accelerated-phase or blast-crisis phase CML. Clinical trial participation should help establish the optimal sequence of these options.
For patients resistant to the tyrosine kinase inhibitor, omacetaxine mepesuccinate (a cephalotaxine, formerly known as homoharringtonine, with activity independent of BCR/ABL) has shown a hematologic response rate of 67% and a median progression-free survival of 7 months in a small, phase II study of 46 patients.[Level of evidence: 3iiiDiv]
Infusions of buffy-coat leukocytes or isolated T cells obtained by pheresis
from the bone marrow transplant donor have induced long-term remissions in more
than 50% of patients who relapse following allogeneic transplant. The efficacy
of this treatment is thought to be the result of an immunologic graft-versus-leukemia
effect. This treatment is most effective for patients whose relapse is
detectable only by cytogenetics or molecular studies and is associated with
significant graft-versus-host disease. After relapse from allogeneic SCT, some patients will
also respond to interferon alpha. Most patients will respond to imatinib mesylate with durable (>1 year) cytogenetic and molecular responses. (These patients had not previously received imatinib.)
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with relapsing chronic myelogenous leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Baccarani M, Saglio G, Goldman J, et al.: Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108 (6): 1809-20, 2006.
Marin D, Milojkovic D, Olavarria E, et al.: European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 112 (12): 4437-44, 2008.
Jabbour E, Kantarjian HM, O'Brien S, et al.: Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early chronic phase chronic myeloid leukemia: what is the optimal response? J Clin Oncol 29 (32): 4260-5, 2011.
Soverini S, Hochhaus A, Nicolini FE, et al.: BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118 (5): 1208-15, 2011.
Parker WT, Lawrence RM, Ho M, et al.: Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy. J Clin Oncol 29 (32): 4250-9, 2011.
le Coutre PD, Giles FJ, Hochhaus A, et al.: Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance: 24-month follow-up results. Leukemia 26 (6): 1189-94, 2012.
Hochhaus A, Baccarani M, Deininger M, et al.: Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22 (6): 1200-6, 2008.
Guilhot F, Apperley J, Kim DW, et al.: Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 109 (10): 4143-50, 2007.
Kantarjian HM, Giles FJ, Bhalla KN, et al.: Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood 117 (4): 1141-5, 2011.
Kantarjian H, Cortes J, Kim DW, et al.: Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood 113 (25): 6322-9, 2009.
Jabbour E, Jones D, Kantarjian HM, et al.: Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations. Blood 114 (10): 2037-43, 2009.
Hughes T, Saglio G, Branford S, et al.: Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol 27 (25): 4204-10, 2009.
Kantarjian H, Pasquini R, Lévy V, et al.: Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer 115 (18): 4136-47, 2009.
Cortes JE, Kantarjian HM, Brümmendorf TH, et al.: Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 118 (17): 4567-76, 2011.
Khoury HJ, Cortes JE, Kantarjian HM, et al.: Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 119 (15): 3403-12, 2012.
Cortes JE, Kantarjian H, Shah NP, et al.: Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 367 (22): 2075-88, 2012.
Dazzi F, Szydlo RM, Craddock C, et al.: Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 95 (1): 67-71, 2000.
Pigneux A, Devergie A, Pochitaloff M, et al.: Recombinant alpha-interferon as treatment for chronic myelogenous leukemia in relapse after allogeneic bone marrow transplantation: a report from the Société Française de Greffe de Moelle. Bone Marrow Transplant 15 (6): 819-24, 1995.
Olavarria E, Ottmann OG, Deininger M, et al.: Response to imatinib in patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia 17 (9): 1707-12, 2003.
Kantarjian HM, O'Brien S, Cortes JE, et al.: Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood 100 (5): 1590-5, 2002.
Hess G, Bunjes D, Siegert W, et al.: Sustained complete molecular remissions after treatment with imatinib-mesylate in patients with failure after allogeneic stem cell transplantation for chronic myelogenous leukemia: results of a prospective phase II open-label multicenter study. J Clin Oncol 23 (30): 7583-93, 2005.
This information was last updated on May 23, 2014.
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