Chronic Myelogenous Leukemia (CML) Treatment & Management

Updated: Sep 24, 2018
  • Author: Emmanuel C Besa, MD; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP  more...
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Treatment

Approach Considerations

The goals of treatment of chronic myelogenous leukemia (CML) are threefold and have changed markedly in the past 10 years. They are as follows:

  1. Hematologic remission (normal complete blood cell count (CBC) and physical examination (ie, no organomegaly)

  2. Cytogenetic remission (normal chromosome returns with 0% Philadelphia chromosome–positive (Ph+) cells)

  3. Molecular remission (negative polymerase chain reaction [PCR] result for the mutational BCR/ABL mRNA), which represents an attempt for cure and prolongation of patient survival

Typically, CML has three clinical phases: an initial chronic phase, during which the disease process is easily controlled; then a transitional and unstable course (accelerated phase); and, finally, a more aggressive course (blast crisis), which is usually fatal. In all three phases, supportive therapy with transfusions of red blood cells or platelets may be used to relieve symptoms and improve quality of life.

The chronic phase varies in duration, depending on the maintenance therapy used: it usually lasts 2-3 years with hydroxyurea (Hydrea) or busulfan therapy, but it may last for longer than 9.5 years in patients who respond well to interferon-alfa therapy. Furthermore, the advent of tyrosine kinase inhibitor (TKI) therapy has dramatically improved the duration of hematologic and, indeed, cytogenetic remissions. For most patients with chronic-phase CML who are treated with TKIs, median survival is expected to approach normal life expectancy  [1]

In Western countries, 90% of patients with CML are diagnosed in the chronic phase. These patients’ white blood cell (WBC) count is usually controlled with medication (hematologic remission). The major goal of treatment during this phase is to control symptoms and complications resulting from anemia, thrombocytopenia, leukocytosis, and splenomegaly. The standard treatment of choice is the first-generation TKI imatinib mesylate (Gleevec), which is a specific small-molecule inhibitor of BCR/ABL in all phases of CML.

The second-generation TKIs nilotinib (Tasigna), dasatinib (Sprycel), and bosutinib (Bosulif) are approved as first-line treatment for CML in the chronic phase. Although all those agents produce a higher rate of deep molecular response and provide better early control of disease than imatinib, the benefits and risks of these newer agents compared with imatinib, as well as their comparative long-term safety profiles, have not yet been established. [15, 16]

A significant “adverse effect” of imatinib is its high cost (approximately $100,000 annually). A generic formulation is available, but its efficacy has been questioned. [17] Moreover, current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely. Successful discontinuation of TKIs has been reported, however, and the National Comprehensive Cancer Network (NCCN) has published criteria for discontinuing TKI therapy. [59]

The European Stop TKI Study (EURO-SKI), found that stopping TKI therapy is feasible and that about half of patients remain free from relapse after 2 years of follow-up. In EURO-SKI, the optimal duration of TKI therapy prior to discontinuation was 5.8 years or longer. [18]  The NCCN guidelines list a minimum of 3 years of approved TKI therapy as a criterion. [59]

Some patients with CML progress to a transitional or accelerated phase, which may last for several months. The survival of patients diagnosed in this phase is 1-1.5 years. This phase is characterized by poor control of blood counts with myelosuppressive medication and the appearance of peripheral blast cells (≥15%), promyelocytes (≥30%), basophils (≥20%), and platelet counts less than 100,000 cells/μL unrelated to therapy.

Many of the treatment decisions in CML, including possible hematopoietic stem cell transplantation [19] and investigative options for younger patients, are extremely complex and in constant flux. Individualized decisions should be made in conjunction with consultation with physicians familiar with the recent literature. New agents that are currently under study may prolong the survival of patients with CML and offer the possibility of eventual cure. Physicians should refer their patients to tertiary care centers for clinical trials involving these therapies.

For more information, see the Medscape articles Chronic Myelogenous Leukemia Treatment Protocols.

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Imatinib Mesylate

Imatinib mesylate (Gleevec) is a tyrosine kinase inhibitor (TKI) that inhibits the abnormal bcr-abl tyrosine kinase created by the Philadelphia (Ph1) chromosome translocation abnormality. Imatinib inhibits proliferation and induces apoptosis in cells positive for BCR/ABL. [3, 4, 7, 20, 21]

For patients with chronic-phase CML, imatinib at 400 mg/day is the best dosage for primary therapy, because it induces a complete hematologic response in almost all patients and causes a high cytogenetic response rate. With imatinib at 400 mg/day orally in patients with newly diagnosed Ph1-positive CML in the chronic phase, the complete cytogenetic response rate is 70% and the estimated 3-year survival rate is 94%.

With higher doses of 800 mg/day, the complete cytogenetic response rate increases to 98%, the major molecular response rate is 70%, and the complete molecular response rate is 40-50%. Despite those improved early responses, however, randomized phase III studies suggest that higher-dose imatinib was not associated with lower rates of disease progression than imatinib, 400 mg, but was associated with higher rates of dose interruption, reduction, or discontinuation due to grade 3 or 4 adverse events. [59]

A study of imatinib in patients with newly diagnosed chronic phase CML found that imatinib maintained efficacy over median follow-up of 10.9 years, without unacceptable cumulative or late toxic effects. The IRIS (Randomized Study of Interferon vs STI571) trial was an open-label crossover trial that randomly assigned patients to receive either imatinib or interferon alfa plus cytarabine. Of patients assigned to imatinib, 48.3% completed study treatment with it, and 82.8% had a complete cytogenetic response. The estimated 10-year survival rate was 83.5%. [15]

Santos et al reported that the use of erythropoietic-stimulating growth factors with imatinib did not impact response rates or survival but increased risk for thrombosis. The presence of severe anemia in these patients was associated with worse survival and response. [22]

Kantarjian et al reported that in patients in the chronic phase who had failure or intolerance of interferon treatment, treatment with imatinib resulted in a complete hematologic response in 430 of 454 patients (95%), with a major cytogenetic response (ie, 0-35% of cells in metaphase positive for the Ph1 chromosome) in 60% of patients; 41% had a total response. [4] Among the study patients with features of accelerated-phase CML (n=17), rates of cytogenetic and hematologic responses were 59% and 88%, respectively and among those with features of blastic-phase CML (n=12), rates were 75% and 92%, respectively.

Talpaz et al reported that among 235 patients with accelerated-phase CML, treatment with imatinib yielded a hematologic response in 82% of patients (sustained in 69% and complete in 34%) and major cytogenetic response in 24% (complete in 17%). [6]

Sawyers et al found that among patients in myeloid blast crisis (260 patients), treatment with imatinib resulted in sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. Major cytogenetic responses occurred in 16% of patients, with 7% of the responses being complete. [23]

A study in 1106 patients with newly diagnosed, chronic-phase CML concluded that in terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated-phase or blast-crisis CML, imatinib is superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed, chronic-phase CML. [24] The estimated rates of complete cytogenetic response were 76.2% for the imatinib group and 14.5% in the interferon alfa group. [24]

The estimated rate of a major cytogenetic response at 18 months was 87.1% in the imatinib group and 34.7% in the group given interferon alfa plus cytarabine. At 18 months, the estimated rate of freedom from progression to accelerated-phase or blast-crisis CML was 96.7% in the imatinib group and 91.5% in the combination-therapy group. Imatinib was better tolerated than combination therapy. [24]

Molecular remission is the goal as measured by PCR. Continuation of the drug is important because approximately 20% of patients lose complete cytogenic response, at a rate of 1.4 per 100 person-years. This is due to poor adherence or poor tolerance of the drug in patients who had an adherence rate of less than 85% as the main reason for complete cytogenic response loss. [25]

Treatment of patients with CML in the accelerated phase or in blast crisis has yielded dismal results. Although imatinib can induce a hematologic response in 52-82% of patients, the response is sustained for at least 4 weeks in only 31-64% of patients. The complete response rate is lower, at 7-34% of patients. Karyotypic response occurs in 16-24%, and complete cytogenetic response is observed in only 17%. [23] Higher doses (ie, 600 mg/d) result in improved response rates, cytogenetic response, and disease-free and overall survival.

Resistance of CML cells to imatinib occurs through multiple mechanisms such as overexpression of BCR/ABL and mutations of the abl gene. [8, 9, 26]  Kinase-domain mutations in BCR/ABL represent the most common mechanism of secondary or acquired resistance to imatinib, accounting for 50-90% of cases; 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.

Patients whose CML demonstrates resistance to imatinib should be switched to a different TKI and considered for hematopoietic stem cell transplantation. [59, 60]

Renal damage is an important adverse effect of imatinib. A study by Marcolino et al found that imatinib therapy in non–clinical trial patients with CML was associated with potentially irreversible acute kidney injury, and that long-term treatment may cause a clinically relevant decrease in the estimated glomerular filtration rate (GFR). [27]

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Newer Tyrosine Kinase Inhibitors

The second-generation tyrosine kinase inhibitors (TKIs) dasatinib (Sprycel), nilotinib (Tasigna), and bosutinib (Bosulif) are more potent inhibitors of BCR/ABL than imatinib. Moreover, they exhibit significant activity against all resistant mutations except the BCR/ABL/T315I mutation. All three have been approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with newly diagnosed Philadelphia chromosome–positive (Ph1+) chronic-phase CML, as well as for chronic-phase CML resistant or intolerant to prior therapy that included imatinib. [28] 29 Dasatinib and bosutinib are also FDA-approved for blast-phase Ph1+ CML in patients resistant to or intolerant of other therapies, including imatinib. [30]

Jabbour and colleagues found that second-generation TKIs induced higher rates of early complete cytogenic response (CCyR) and major molecular response than imatinib. The authors also state that CCyR is a major determinant of CML outcome, regardless of whether major molecular response is achieved or not. [31]

Compared with these second-generation agents, imatinib has relatively low potency and inhibits its target at micromolecular rather than nanomolar concentrations. In addition, imatinib has increased susceptibility to resistance through a number of mutations in the BCR-ABL target. [32]

That said, these new tyrosine kinase inhibitors are not without their drawbacks and adverse events. Dasatinib has been associated with pleural effusions and pulmonary arterial hypertension, [33] while nilotinib has been linked to biochemical changes in liver function and QT-interval prolongation. Development of resistance may also occur with these agents.

Moreover, imatinib is still very effective. It is also less expensive than the new tyrosine kinase inhbitors, and will go out of patent in the near future. Consequently, it may survive the challenge posed by newer agents because of a favorable balance of cost and efficacy. [34] Using the MD Anderson prognostic factors scoring may help in identifying the few patients requiring the more expensive second-generation tyrosine kinase inhibitors for first-line use. [35]

A study by Verma et al found that second malignancies occur in a small percentage of patients receiving TKI treatment for hematologic malignancies, mostly CML. No evidence suggests, however, that exposure to these inhibitors increases the risk of developing second malignancies. [36]

Dasatinib

Dasatinib has been shown to be more effective in inducing molecular remission than imatinib. In a comparison of dasatinib with imatinib in 519 patients with newly diagnosed chronic-phase CML, the rate of confirmed complete cytogenetic response after a minimum follow-up of 12 months was 77% with dasatinib versus 66% with imatinib. [37]

A study by Cortes et al that compared dasatinib 100 mg daily or 50 mg twice daily for at least 3 months as initial therapy for early chronic-phase CML found no difference in outcome between the 2 dosages. [38] Of the 50 patients in the study, 49 (98%) achieved a complete cytogenetic response and 41 (82%) achieved a major molecular response. The projected event-free survival rate at 24 months was 88%, and all patients were alive after a median follow-up time of 24 months. [38]

In June 2013, the FDA approved a change to the product labeling of dasatinib, updating efficacy and safety information to include 3-year efficacy and safety data for patients with newly diagnosed Philadelphia (Ph) chromosome–positive CML that is in the chronic phase. [39] The new labeling also includes 5-year data for patients with chronic-phase Ph chromosome–positive CML that is imatinib-resistant or imatinib-intolerant.

The 3-year data are from the DASISION (Dasatinib vs Imatinib Study in Treatment-Naïve CML Patients) study, an ongoing open-label randomized phase 3 trial. [40] At 12 months, the confirmed cytogenetic response rate (CCyR) was 77% in patients treated with dasatinib and 66% in those treated with imatinib. At 36 months, a higher percentage of patients in the dasatinib group had confirmed CCyR (83% vs 77%). The rate of major molecular response (MMR) was also higher for dasatinib at both 12 and 36 months.

The 5-year data are from an open-label phase 3 dose-optimization study in which fewer than 5% of dasatinib patients had transformed to accelerated or blast-phase CML by 5 years. [39] The primary endpoint of the study was major cytogenetic response in patients who were resistant to or intolerant of imatinib. This endpoint was achieved by 63% of such patients who were receiving dasatinib at 2 years.

In a study of 670 patients with imatinib-resistant/-intolerant CML in chronic phase, Shah et al found that treatment with dasatinib (in 4 different regimens) improved survival, particularly among those who achieved BCR/ABL transcripts of 10% or less by 3 months. [41]

Estimated 6-year progression-free survival (PFS) rates were 49%, 51%, 40%, and 47% for the 100 mg once daily, 50 mg twice daily, 140 mg once daily, and 70 mg twice daily dosage groups, respectively. [41] Notably, estimated 6-year PFS rates were 68% for BCR/ABL transcripts of 1% or less, 58% for BCR/ABL greater than 1% up to 10%, and 26% for BCR/ABL greater than 10%. Estimated 6-year overall survival rates were 71% for 100 mg once daily, 74% for 50 mg twice daily, 77% for 140 mg once daily, and 70% for 70 mg twice daily.

Nilotinib

Nilotinib has been found superior to imatinib in patients with newly diagnosed chronic-phase Ph+ CML. [42] In addition, Kantarjian et al reported that nilotinib maintained better efficacy during a minimum follow-up of 24 months. Compared with imatinib, significantly more patients receiving nilotinib achieved a major molecular response, or a complete molecular response at any time, and fewer progressed to accelerated or blast phase. These authors concluded that these results support the use of nilotinib as a first-line treatment option. [43]

In March 2018, FDA has approved nilotinib for first- and second-line treatment of pediatric patients aged 1 year and older with Ph+ CML-CP. Approval was based on a cohort of 69 pediatric patients with Ph+ CML-CP enrolled across 2 trials. Patients were either newly diagnosed or resistant/intolerant to prior treatment with a tyrosine kinase inhibitor.

The major molecular response (MMR) in newly diagnosed patients was 60% at 12 cycles, with 15 patients achieving MMR. The cumulative MMR in this group was 64% by cycle 12, and the median time to first MMR was 5.6 months. In the resistant/intolerant group, the MMR rate was 40.9% at 12 cycles, with 18 patients being in MMR. The cumulative MMR rate in this group was 47.7% by cycle 12, and the median time to first MMR was 2.8 months. [64]

Bosutinib

Approval of bosutinib was based on a single-arm, open-label, multicohort, phase I/II study of more than 500 patients with imatinib-resistant or -intolerant Ph+ CML. Separate cohorts were established for chronic-, accelerated-, and blast- phase CML previously treated with 1 or more prior tyrosine kinase inhibitors (ie, imatinib, imatinib followed by dasatinib and/or nilotinib).

In 118 patients with chronic-phase CML, a major cytogenetic response was attained in 32% of patients, a complete cytogenetic response was attained in 24%, and a complete hematologic response was attained in 73%. At 2 years, the progression-free survival rate was 73% and the estimated overall survival rate was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. [44]

In December 2017, the FDA also gave accelerated approval for newly diagnosed chronic-phase Ph+ CML. Approval was based on an ongoing, multinational, phase III study in 536 patients with newly diagnosed chronic-phase CML, in which the major molecular response rate at 12 months (the primary end point) was significantly higher with bosutinib versus imatinib (47.2% vs 36.9%, respectively), as was the complete cytogenetic response (CCyR) rate by 12 months (77.2% v 66.4%, respectively. [45]

Ponatinib

The third-generation TKI ponatinib (Iclusig) was approved by the FDA in December 2012 for use in patients with CML that had relapsed or become refractory to other therapies. Many of these patients will have developed a T315I mutation, which confers resistance to imatinib and other tyrosine kinase inhibitors. [46, 47, 48]

In the phase 2 PACE (Ponatinib PH+ ALL [acute lymphoblastic leukemia] and CML Evaluation) trial, the drug successfully treated patients with chronic-phase CML (major cytogenetic response in 55% of cases, including 70% of patients with the T315I mutation, within 12 months), with accelerated-phase CML (major hematologic response in 57% of cases within 6 months), or with blast-phase CML/Ph1-positive ALL (major hematologic response in 34% of cases within 6 months). [46, 47, 48]

In October 2013, at the FDA’s request, ponatinib was temporarily removed from the market because of safety concerns. The FDA cited an increased risk for life-threatening blood clots and severe narrowing of blood vessels. [49, 50] In December 2013, the FDA allowed resumption of marketing, since the benefits of response to ponatinib far outweigh the risk of complications from the drug. [51, 52]

However, the FDA required the addition of a black box warning regarding arterial and venous thrombosis and occlusions, which have occurred in at least 27% of patients in early trials, typically within 2 weeks of starting ponatinib. In addition, the FDA limited the indications for use of ponatinib to the following [52] :

  • Adult patients with T315I -positive CML in chronic, accelerated, or blast phase (or T315I -positive, Ph1-positive ALL)

  • Adult patients with chronic, accelerated, or blast phase CML for whom no other TKI therapy is indicated

The FDA has also revised the dosing recommendations to state that the optimal dose of ponatinib has not been identified. The recommended starting dose remains 45 mg once daily, but additional information is included regarding dose decreases and discontinuations.

The author agrees that the FDA acted appropriately in limiting the use of ponatinib but making it available from the market while experts determine the optimal dose and dosing schedule for lessening toxicity from ponatinib without compromising its efficacy. This is a process that many other agents have had to undergo, following FDA approval. The T315I mutation for which ponatinib is effective is very rare, affecting only a small minority of CML patients. Nevertheless, for some of those patients, ponatinib has proved lifesaving.

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Protein Translation Inhibitors

In October 2012, the US Food and Drug Administration (FDA) approved omacetaxine (Synribo). Omacetaxine is a protein translation inhibitor that is indicated for chronic- or accelerated-phase CML with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors (TKIs) (eg, dasatinib, nilotinib, imatinib).

Approval was based on combined data from 2 phase 2, open-label, multicenter studies. Pooled data included patients (n=111) who had received two or more TKIs and showed evidence of resistance or intolerance. In patients with chronic-phase CML taking omacetaxine, 18% attained a major cytogenetic response (MCyR) (mean time to MCyR onset, 3.5 mo). The median duration of MCyR was 12.5 months. Of patients with accelerated-phase CML who received omacetaxine, 14% attained a major hematologic response (MaHR); mean time to MaHR was 2.3 mo and mean duration of MaHR was 4.7 months. [53]

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Myelosuppressive Therapy

Myelosuppressive therapy was formerly the mainstay of treatment to convert a patient with CML from an uncontrolled initial presentation to one with hematologic remission and normalization of the physical examination and laboratory findings. However, it may soon fall out of favor as the new agents prove to be more effective, with fewer adverse events and longer survival.

Hydroxyurea

Hydroxyurea (Hydrea), an inhibitor of deoxynucleotide synthesis, is the most common myelosuppressive agent used to achieve hematologic remission. The initial blood cell count is monitored every 2-4 weeks, and the dose is adjusted depending on the WBC and platelet counts. Most patients achieve hematologic remission within 1-2 months.

This medication causes only a short duration of myelosuppression; thus, even if the counts go lower than intended, stopping treatment or decreasing the dose usually controls the blood counts. Maintenance with hydroxyurea rarely results in cytogenetic or molecular remissions.

European Society for Medical Oncology (ESMO) guidelines suggest that hydroxyurea (40 mg/kg daily) may be used as initial therapy, before confirmation of the BCR–ABL1 fusion in patients with immediate need for therapy because of high leukocyte counts or clinical symptoms. TKI therapy should be started immediately after confirmation of BCR–ABL1 positivity, and the hydroxyurea dose tapered before discontinuation. [60]

Busulfan

Busulfan (Myleran) is an alkylating agent that has traditionally been used to keep the WBC counts below 15,000 cells/µL. However, the myelosuppressive effects may occur much later and persist longer, which makes maintaining the numbers within normal limits more difficult. Long-term use can cause pulmonary fibrosis, hyperpigmentation, and prolonged marrow suppression lasting for months.

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Leukapheresis

Leukapheresis using a cell separator can lower WBC counts rapidly and safely in patients with WBC counts greater than 300,000 cells/µL, and it can alleviate acute symptoms of leukostasis, hyperviscosity, and tissue infiltration.

Leukapheresis usually reduces the WBC count only temporarily. Thus, it is often combined with cytoreductive chemotherapy for more lasting effects.

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Interferon alfa

In the past, interferon alfa was the treatment of choice for most patients with CML who were too old for bone marrow transplantation (BMT) or who did not have a matched bone marrow donor. With the advent of tyrosine kinase inhibitors, interferon alfa is no longer considered first-line therapy for CML. It may be used in combination with newer drugs for treatment of refractory cases.

A study by Simonsson et al found that the addition of even relatively short periods of pegylated interferon alfa2b to imatinib increased the major molecular response rate at 12 months of therapy. Lower doses of pegylated interferon alfa2b may enhance tolerability while retaining efficacy and could be considered in future studies. [54]

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Transplantation

Allogeneic bone marrow transplantation (BMT) or stem cell transplantation is currently the only proven cure for 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.

BMT should be considered early in young patients (< 55 y) who have a matched sibling donor. [55, 56] All siblings should be typed for human leukocyte antigen (HLA)-A, HLA-B, and HLA-DR. If no match is available, the HLA type can be entered into a bone marrow registry for a completely matched unrelated donor.

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.

The mortality rate associated with BMT is 10-20% or less with a matched sibling and 30-40% with an unrelated donor. The bone marrow registry approximates the cure rate for patients with CML at 50%.

Transplantation has been relegated to patients who do not achieve molecular remissions or show resistance to imatinib and failure of second-generation bcr-abl kinase inhibitors such as dasatinib. Previous exposure to imatinib before transplantation does not adversely affect posttransplant outcomes such as overall survival and progression-free survival.

A retrospective analysis that included 70 patients with CML (44% in accelerated phase or blast crisis) who had received imatinib before stem cell transplantation showed 90% engraftment and estimated transplant-related mortality of 44% and estimated relapse mortality of 24% at 24 months. Graft versus host disease rates were 42% for acute and 17% for chronic. [57]

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.

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.

The advent of imatinib therapy has overshadowed allogeneic hematopoietic stem cell transplantation in newly diagnosed CML. However, it has been suggested that patients with a poor-risk Sokal score (see Prognosis) but good risk for allogeneic hematopoietic stem cell transplantation be transplanted early or upfront. No current consensus exists on these issues. However, a widely accepted consensus is that patients who progress beyond chronic phase on imatinib should be offered hematopoietic stem cell transplantation if this is an option.

With patients in blast crisis who are imatinib naive, the drug is used in combination with induction regimens similar to those used in acute myelogenous or lymphoblastic leukemia. However, because a high percentage of imatinib-resistant mutations exist in these patients, relapses occur more frequently and at an earlier time from induction. Thus, all efforts are made to perform an allogeneic hematopoietic stem cell transplantation as soon as possible.

Most patients with minimal residual disease (MRD) after transplantation require interferon maintenance therapy. Alternatively, they may require a reinfusion of T cells collected from the donor.

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Splenectomy

Splenectomy and splenic irradiation have been used in patients with large and painful spleens, usually in the late phase of CML. This is rarely needed in patients whose disease is well controlled.

Some authors believe that splenectomy accelerates the onset of myeloid metaplasia in the liver. In addition, splenectomy is associated with high perioperative morbidity and mortality rates because of bleeding or thrombotic complications.

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Long-Term Monitoring

The cytogenetic response is monitored every 3-6 months by karyotyping or by fluorescence in situ hybridization (FISH) to count the percentage of bone marrow cells with Ph1-positive cells in bone marrow. Long-term monitoring using peripheral blood for FISH and quantitative reverse transcriptase PCR (RT-PCR) for BCR/ABL messenger RNA appear to be reliable methods for monitoring responses to tyrosine kinase inhibitor therapy in all phases of CML. [58]

The goal is 100% normal cells after 1-2 years of therapy. Patients with MRD (BCR/ABL positive) should be kept on maintenance therapy as long as they continue to have MRD.

Cytogenetic improvement has been observed in 70% of patients treated for longer than 3 months, with the median of Ph1-positive cells declining from 100% to 65% (range 0-95%). Complete suppression of the Ph1 chromosome was observed in 20% of patients.

More than 80% of newly diagnosed patients with CML in the chronic phase will achieve a complete cytogenetic response with the standard dose of 400 mg/day 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 complete cytogenetic response 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 remained constant over the years at an average of 2%.

High Sokal risk predicts poorer outcome, but responses during treatment generally override pretherapeutic prognostic variables. When less-sensitive tests become negative, more-sensitive tests are done (ie, cytogenetics and FISH); thus, monitoring should be tailored to the level of response attained by a given patient.

The standard therapeutic milestones to be achieved are as follows:

  1. At 3 months: complete hematologic response (normal complete blood count and no evidence of extramedullary disease)

  2. At 6 months: minor cytogenetic response (36% to 65% of cells Ph1+)

  3. At 12 months: major cytogenetic response (0% to 35% Ph1+)

  4. At 18 months: complete cytogenetic response (0% Ph1+)

Failure to achieve these milestones should trigger a reassessment of the therapeutic strategy. Most patients with complete cytogenetic response continue to have positive RT-PCR findings, 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 needs to be confirmed in further studies.

The criteria for major molecular response is ≥3-log reduction of BCR/ABL mRNA, and for complete molecular response 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 complete cytogenetic response, patients can be classified according to their molecular response into those with major molecular response (≥3-log) or < 3-log reduction of transcripts (98% vs 90% progression-free survival).

Limited data are available on patients with complete cytogenetic response or major molecular response 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 any level. Primary hematologic resistance to imatinib occurs in approximately 5% of patients who fail to achieve complete histologic remission, 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.

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