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Chronic myeloid leukemia
Treatment

At initial diagnosis, consideration should be given to referral of patients younger than age 60 years to centers with bone marrow transplantation when appropriate donors are available. This should be done during the first year of diagnosis.

Response criteria

Hematologic response

In chronic phase CML, a hematologic response was defined as a 50% reduction in WBC counts from baseline sustained for at least 2 weeks. A Complete Hematologic Response (CHR) was defined as WBC < 10,000 per mm3and platelet count < 450,000 per mm3 maintained for at least 4 weeks.

In blast crisis CML, a hematologic response is defined as a decrease in bone marrow blast count to < 5%, the disappearance of blasts in the peripheral blood, an absolute neutrophil count > 1000 cells/mm3and platelet count > 100,000 cells/mm3. Patients who did not meet the criteria for a complete hematologic response may be categorized according to marrow response.

A marrow response is defined as either a decrease in the blast count to < 5% or between 5-15% regardless of peripheral blood cell counts.

  • Disease progression is defined as an increase in marrow blasts > 15%, increase in peripheral blood blasts > 5% or WBC > 20,000 cells/mm3.
  • A relapse is defined as evidence of disease progression or death.

Cytogenetic response

Cytogenetic responses (CR) were defined in terms of percentage of cells in metaphase existing within the bone marrow that were Philadelphia (Ph) chromosome positive. These responses were based upon a sample size of twenty cells in metaphase.

  • A Complete Cytogenetic Response (CCR) was defined as no Ph(+) cells.
  • A partial CR was defined as < 35% cells that were Ph(+).
  • A minor CR was defined as 35-65% cells that were Ph(+).
  • A lack of CR was identified when >65% cells were Ph(+).
  • A major cytogenetic response (MCR) is comprised of complete and partial responses.

Molecular response

Standardization studies are ongoing and definition of molecular response currently vary.

  • Complete molecular response: no detectable bcr-abl transcripts by RT-PCR.
  • Major molecular response: 3-log reduction in the level of bcr-abl transcripts or bcr-abl/abl ratio 0.05%.

Chronic phase

Imatinib mesylate (Glivec)

Imatinib mesylate (STI571) also know as Glivec specifically inhibits the proliferation of CML-derived cell-lines and the clonogenic growth of cells from the bone marrow of patients with CML.

It has demonstrated significant activity in patients with CML in all phases of the disease, whether they have received prior therapy or not.

The standard dose of imatinib mesylate is 400 mg daily for chronic phase and 600 mg for accelerated and blastic phases. At this time, the duration of therapy is unclear. A minority of patients have reached undetectable levels of disease by PCR, and few have discontinued therapy. Thus, until further evidence becomes available, patients should continue therapy indefinitely.

Benefit

  • Among patients with chronic - phase CML for whom prior IFN-α therapy failed, 65%-85% of patients achieved a major cytogenetic remission, including 45%-80% with a complete cytogenetic remission. The estimated disease progression-free survival is 89% at 18 months.
  • Among patients treated in early chronic-phase CML who had not received prior therapy, the rate of complete cytogenetic response is 75%-90%.

All patients have to be evaluated with cytogenetic analysis before the start of therapy, and a baseline quantitative polymerase chain reaction (PCR) analysis is useful. A cytogenetic analysis every 3 to 6 months during the first year and every 6 to 12 months thereafter is recommended. Quantitative PCR is recommended every 3 to 6 months.

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Allogeneic bone marrow transplantation

Allogeneic BMT is potentially curative in CML, although late relapses have been reported.

Benefits

  • Long- term survival rates of 50%-80% and disease free survival rates of 30%-70% can be achieved in the chronic phase.

Risks

  • 40-50% mortality rate.

Predictors of response

  • Early BMT within the first 1-3 years after diagnosis may be associated with a better outcome than BMT later in the course of disease.

  • Younger patients also have a better outcome than older patients, with those younger than age 20 having the best prognosis.

  • The use of the Gratwohl score helps to separate those patients who may have a better outcome from those who will not.

Alternatives to matched-related donors

For patients who do not have a matched-related donor, matched unrelated donor (MUD) transplants are reasonable alternatives.

Benefits

The 9-year experience from the National Marrow Donor Program in 1,432 patients reported a 3-year survival rate of 37.5%. Early transplantation results in better outcome, with patients transplanted in chronic phase having a 3-year disease-free survival of 63%.

Relapse after BMT

Donor leukocyte reinfusions are the most effective strategy to treat patients who relapse after BMT. With this strategy, 70%-80% of patients can achieve a cytogenetic complete response; the best results are achieved when patients are treated during cytogenetic relapse.

Imatinib mesylate has also been effective for patients who relapse after BMT. A complete hematologic response in > 70% of patients and a cytogenetic response in 58% have been reported, with the best responses obtained in patients relapsing in chronic phase.

Autologous BMT

Treatment recommendations

  • No compatible related donor Most patients (> 70%) do not have a related HLA-compatible donor

  • Matched-related or one-antigen-mismatched donor

  • MUD

  • Imatinib mesylate failure

Benefits

  • Although 40%-70% of patients can achieve some degree of suppression of Ph chromosome- positive cells upon engraftment of the autologous transplant, this result is usually short-lived, and most patients relapse within 1 year.

  • Some patients previously refractory to rIFN-α may regain sensitivity after autologous BMT.

The role of autologous BMT with cells collected after complete response to imatinib mesylate and with imatinib mesylate-based therapy after transplantation is currently being investigated.

Hydroxyurea

Standard drug therapy (e.g. with hydroyxurea) is administered to diminish WBC count to approximately 10,000 per cubic millimeter without producing marrow hypoplasia. Leukapheresis and platelet pheresis can also be used to rapidly lower extremely high WBC and platelet counts although this is only of temporary benefit and is rarely required in adults in chronic phase.

Indications

Its use should be limited to temporary control of hematologic manifestations before definitive therapy (e.g. imatinib mesylate, stem-cell transplantation) is instituted.

Busulfan

Busulfan is usually given at a dose of 0.1 mg/kg/d until the WBC count decreases by 50%, at which point the dose is reduced by 50%. Therapy is discontinued when the WBC count drops below 20 ?109/L and is restarted when it rises above 50 ?109/L.

Busulfan is associated with lung, marrow, and heart fibrosis and can cause an Addison-like disease. In 10% of patients, prolonged myelosuppression may be observed.

Indications

Its use should be limited to temporary control of hematologic manifestations before definitive therapy (e.g. imatinib mesylate, stem-cell transplantation) is instituted.

Benefit

Both busulfan and hydroxyurea can control the hematologic manifestations of CML in more than 70% of all patients, although hydroxyurea results in a longer duration of chronic phase and overall survival than does busulfan. Neither drug significantly reduces the percentage of cells bearing the Ph chromosome, and, therefore, transformation to the blastic phase is unchanged.

Interferon alfa

Interferon alfa may produce partial or complete remissions in chronic phase CML. Cytogenetic responses have been reported in up to 20% of patients, with delay of disease progression and prolongation of overall survival.

Benefits

  • A complete hematologic response is induced in 70%-80% of patients

  • A cytogenetic response is achieved in 40%-60% of patients (in which there is some degree of suppression of Ph chromosome-positive cells)

  • A complete cytogenetic response in 5% of patients

  • A major cytogenetic response in approximately 15%

  • Complete cytogenetic responses are durable in ≥ 80% of cases. These patients also have a 10-year survival rate of 75% or more

The addition of cytarabine (Ara-C) can improve the rate of both complete and major cytogenetic responses but with increased toxicity.

Accelerated or blastic phases

Imatinib mesylate

Benefits

In accelerated phase:

  • 71% of patients treated with 600 mg/d of imatinib mesylate had a hematologic response.

  • The major cytogenetic response rate was 24%, with a time to disease progression of  12 months at 67%.

In blast phase:

  • 52% of patients achieved a hematologic remission and 31% a sustained remission lasting at least 4 weeks with imatinib mesylate.

  • However, the median response duration is only 10 months, even when considering only patients with sustained remission (i.e., lasting at least 4 weeks).

Patients with clonal evolution have a lower probability of response and shorter survival than patients without clonal evolution when treated with imatinib mesylate. Imatinib mesylate is also effective for patients with CML in transformation.

Interferon

Patients with clonal evolution as their only criterion of accelerated disease may respond to interferon, especially when < 16% of metaphases bear the additional abnormality and the cytogenetic abnormality occurs within the first 24 months of diagnosis.

Chemotherapy

Intensive chemotherapy regimens, including high-dose Ara-C and daunorubicin (Cerubidine), induce remissions in only 25%-35% of patients in accelerated or blast phase (median survival durations of 8-18 months and 3 months, respectively).

Patients with a lymphoid blastic phase treated with therapy similar to that given for acute lymphocytic leukemia (i.e. vincristine, doxorubicin, and dexamethasone, with or without cyclophosphamide) have a complete response rate of 60%.

New agents and combination regimens are currently being evaluated. The combination of imatinib mesylate with chemotherapy regimens is under evaluation. The role of cyclophosphamide, Ara-C, farnesyl transferase inhibitors, and topotecan [Hycamtin] are currently being evaluated.

Decitabine is a hypomethylating agent with promising activity in patients in accelerated or blast phase. Decitabine achieved an objective response in 33% of patients in blast phase and 66% of those in accelerated phase. Lower doses of decitabine achieve optimal demethylation with reduced toxicity and are currently being evaluated.

BMT

Compared with those results in patients in chronic phase, results with allogeneic BMT are worse in patients in accelerated or blastic phase, with 4-year survival rates of only 10%-30%.

Patients in accelerated phase (determined on the basis of clonal evolution only) who undergo BMT < 1 year after diagnosis have a 4-year probability of survival of 74%.

Prognosis and survival

The median survival is 4 to 6 years, with a range of less than 1 year to more than 10 years. Survival after development of an accelerated phase is usually less than 1 year and after blastic transformation is only a few months.

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