eMedicine Specialties > Hematology > Stem Cells and Disorders

Chronic Myelogenous Leukemia: Follow-up

Author: Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Coauthor(s): Ulrich Woermann, MD, Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland
Contributor Information and Disclosures

Updated: Feb 6, 2009

Follow-up

Further Inpatient Care

• Allogeneic bone marrow or stem cell transplantation is the best treatment for cure of chronic myelogenous leukemia (CML). Unfortunately, this procedure has a high mortality rate because of the induction and long-term complications. Several types of BMT are available, and most data are from allogeneic transplantations from HLA-matched sibling donors and a few syngeneic transplantations from an identical twin. Data show that allogeneic transplantations have better results than syngeneic transplantations because of some graft versus leukemia effects.
  • Allogeneic BMT is currently the only proven cure for chronic myelogenous leukemia (CML). Ideally, it should be performed in the chronic phase of the disease rather than in the transformation phase or in blast crisis. Candidate patients should be offered the procedure if they have a matched or single–antigen-mismatched related donor available. In general, younger patients fare better than older patients.
  • Allogeneic BMT with matched unrelated donors has yielded very encouraging results in this disease. The procedure has a higher rate of early and late graft failures (16%), grade III-IV acute graft versus host disease (50%), and extensive chronic graft versus host disease (55%). The overall survival rate ranges from 31% to 43% for patients younger than 30 years and from 14% to 27% for older patients. Benefits and risks should be assessed carefully with each patient.
• Autologous BMT is investigational, but, relatively recently, chemotherapy combinations or interferon have been found to induce a cytogenetic remission and allow harvesting of Ph-negative CD34 hematopoietic stem cells from the patient's peripheral blood.
• Other attempts to collect specifically normal stem cells are currently being investigated. The role of allogeneic hematopoietic stem cell transplantation in newly diagnosed chronic myelogenous leukemia (CML) has been relegated to the back with the availability of imatinib therapy. However, it has been suggested that patients with "poor-risk" Sokal scores but good risk for allogeneic hematopoietic stem cell transplantation be transplanted early or upfront, but no current consensus exists on these issues. However, a widely accepted consensus is patients who progress beyond chronic phase on imatinib should be offered hematopoietic stem cell transplantation if this is an option.
• Management of lymphoid and myeloid blast crisis: In patients with chronic myelogenous leukemia (CML) in blast crisis who are imatinib naive, the drug is used in combination to standard acute myelogenous leukemia or acute lymphoblastic leukemia induction-like regimens. However, because a high percentage of imatinib-resistant mutations exists in these patients, relapses occur more frequently and at an earlier time from induction. Thus, all efforts are made to take these patients for an allogeneic hematopoietic stem cell transplantation as possible.

Further Outpatient Care

• Management of early or chronic phase: The standard treatment of choice is now imatinib mesylate (Gleevec), which is a specific small-molecule inhibitor of BCR/ABL in all phases of chronic myelogenous leukemia (CML). Ninety percent of patients with CML in Western countries are diagnosed in the early or chronic phase of the disease.
• More than 80% of newly diagnosed patients with chronic myelogenous leukemia (CML) in the chronic phase will achieve a complete cytogenetic response (CCR) with the standard dose of 400 mg/d of imatinib. The probability of progression-free survival is strongly correlated with the level of response, approaching 100% in those patients who achieve molecular remission (a reduction of BCR/ABL mRNA by at least 3-log at 12 mo).In patients with chronic-phase CML whose interferon therapy had failed, the CCR was 41% at 18 months and 52% at 40 months, with a progression-free survival at 2 years of 76%. Progression to an accelerated phase or blast crisis had a peak at 2 years of 7.6%, but the incidence remains constant over the years at an average of 2%.
  • High Sokal risk predicts poorer outcome, but on-treatment response parameters generally override pretherapeutic prognostic variables. Sokal score (based on age, spleen size, platelet and peripheral blood blast counts) is well correlated with the likelihood of achieving CCR: 91% for low-, 84% for intermediate-, and 69% for high-risk patients.
  • Standard monitoring of response includes full blood counts, cytogenetics (or FISH), and quantitative reverse transcriptase (RT)-PCR for BCR/ABL mRNA. The more sensitive tests are done when the previous less sensitive tests become negative (ie, cytogenetics and FISH), and, thus, they should be tailored to the level of response attained by a given patient.
  • The standard therapeutic milestones to be achieved in the patients are (1) a complete hematologic response (normal CBC and no evidence of extramedullary disease) at 3 months, (2) a minor cytogenetic response (36% to 65% Ph+) at 6 months, (3) a major cytogenetic response (0% to 35% Ph+) at 12 months, and (4) a complete cytogenetic response (0% Ph+) at 18 months.
  • Failure to achieve these milestones should trigger a reassessment of the therapeutic strategy. Most patients with CCR remain positive for RT-PCR, indicating the presence of MRD. Discontinuation of the drug in these patients is usually followed by relapse, suggesting that imatinib fails to eradicate leukemic stem cells in these patients.
  • Early intensification with the use of high doses of imatinib (800 mg/d) or imatinib in combination with cytarabine or interferon alfa may induce higher rates of RT-PCR negativity, but this still needs to be confirmed in further studies.
  • The criteria for major molecular response (MMR) is >3-log reduction of BCR/ABL mRNA, and for complete molecular response (CMR), it is negativity by RT-PCR. Because a good correlation exists between BCR/ABL mRNA in bone marrow and peripheral blood, this can be monitored from peripheral blood samples.
  • At 12 months with CCR, patients can be classified according to their molecular response into those with MMR (>3-log) or <3-log reduction of transcripts (98% vs 90% progression-free survival).
  • Limited data are available on patients with CCR or MMR who discontinued their treatment with imatinib (5 of 6 patients had reappearance of Ph+).
  • Patients should be screened for mutations of the BCR/ABL kinase domain whenever there is an indication of loss of response to imatinib at whichever level. Primary hematologic resistance to imatinib occurs in approximately 5% of cases that fail to achieve complete  histologic remission (CHR), and 15% show primary cytogenetic resistance in the chronic phase. Secondary or acquired resistance (loss of previous response) is 16% at 42 months and increases to 26% in those previously treated with interferon, and is 73-95% in the accelerated or blast phase.

Prognosis

• Historically, the median survival of patients with chronic myelogenous leukemia (CML) from the time of diagnosis was 3-5 years, and, until recently, no known therapy was shown to alter this survival rate. As treatment improved, the need to stage patients according to their prognoses became necessary to justify procedures with high morbidity and mortality, such as BMT.
• Staging of patients is based on several analyses using multiple variate analysis between the association of pretreatment host and leukemic cell characteristics and their corresponding patient's survival. The findings from these studies classify patients into good-risk groups (average survival of 5-6 y), intermediate-risk groups (average survival of 3-4 y), or poor-risk groups (average survival of 2 y). A combined prognostic model, incorporating previous models such as the Sokal score, has been devised using the number of poor-prognosis characteristics: stage 1 is for 0 or 1+, stage 2 is for 2+, stage 3 is for 3 or more, and stage 4 is for diagnosis at blastic phase.
  • Poor prognosis in patients with chronic myelogenous leukemia (CML) is associated with several clinical and laboratory factors, including older age, symptomatic presentation, poor performance status, African American descent, hepatomegaly, splenomegaly, negative Ph chromosome or BCR/ABL, anemia, thrombocytopenia, thrombocytosis, decreased megakaryocytes, basophilia, or myelofibrosis (increased reticulin or collagen).
  • Several therapy-associated factors may indicate a poor prognosis in patients with chronic myelogenous leukemia (CML), including longer time to hematologic remission with myelosuppression therapy, short duration of remission, total dose of hydroxyurea or busulfan, or poor suppression of Ph-positive cells by chemotherapy or interferon alfa therapy.
• The prognosis of patients with chronic myelogenous leukemia (CML) has improved from an expected median survival of 3 years and a 5-year survival rate of less than 20% to a median survival of 5 or more years and a 5-year survival rate of 50-60%. The improvement is due to earlier diagnosis, improved therapy with interferon and BMT, and better supportive care.A German study of 139 low-risk patients with CML, according to the Sokal index, showed that the median survival with busulfan is 6 years (50 patients); with hydroxyurea, 6.5 years (55 patients); and with interferon alfa, approximately 9.5 years (34 patients), indicating improvement in survival with new therapy.
• Some patients with molecular remissions from interferon alfa may be cured, but this can only be established over time.
• The new and active tyrosine kinase inhibitor, imatinib, is associated with a higher response rate and better tolerance of adverse effects. It may replace interferon as first-line therapy. Long-term remissions remain to be seen, and imatinib will be reevaluated in the near future to determine its role in the treatment of chronic myelogenous leukemia (CML).

Patient Education

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose and treat chronic myelogenous leukemia (CML) early with new modalities may be a cause for malpractice charges.

Special Concerns

• The discovery of new agents presently under study, such as tyrosine kinase inhibitor therapy, may prove valuable in prolonging the survival of patients  with chronic myelogenous leukemia (CML) and may provide them with an eventual cure. Physicians should refer their patients to tertiary care centers for clinical trials involving these therapies.
• Development of secondary or acquired imatinib resistance and the mechanisms responsible are due to BCR/ABL mutations. The molecular mechanism for primary imatinib resistance is unknown.
  • Kinase-domain mutations in BCR/ABL represents the most common mechanism of acquired resistance to imatinib occurring in 50-90% of cases, of which 40 different mutations have currently been described. Because imatinib binds to the ABL kinase domain in the inactive, or closed, conformation to induce conformational changes, resistance occurs when the mutation prevents the kinase domain from adopting the specific conformation upon binding.
  • The development of 2 novel BCR/ABL inhibitors, dasatinib (BMS-354825) and AMN107, are more potent inhibitors of BCR/ABL than imatinib, and moreover, they exhibit significant activity against all resistant mutations except BCR/ABL/T315I mutation.

• Search for CME/CE on This Topic »

• Chronic Myeloid Leukemia and BCR-ABL (Genomic Medicine)
• Agnogenic Myeloid Metaplasia With Myelofibrosis (Hematology)
• Thrombocytosis (Pediatrics: General Medicine)
• Leukemias (Ophthalmology)

• Blood and Lymphatic System Center
• Leukemia Causes
• Leukemia Overview
• Leukemia Symptoms
• Leukemia Treatment

• Mental Status Changes Precede Hematopoietic Stem Cell Transplantation
• Survival Rates Greatly Improved for Adolescents and Young Adults With Hematologic Cancers
• EHA 2009: Nilotinib Superior in Chronic Myeloid Leukemia Than Current Standard

• The Biological Basis for Immunotherapy in Patients with Chronic Myelogenous Leukemia
• Persistent Cutaneous Hyperpigmentation After Tyrosine Kinase Inhibition With Imatinib for GIST
• Association Between Imatinib-Resistant BCR-ABL Mutation-Negative Leukemia and Persistent Activation of LYN Kinase

• CML Resource Center
• Chronic Leukemia Resource Center