Chronic Myelogenous Leukemia (CML) Treatment & Management

The goals of treatment of chronic myelogenous leukemia (CML) are threefold and have changed markedly since the advent of tyrosine kinase inhibitor (TKI) therapy. 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 to control symptoms and complications resulting from anemia and thrombocytopenia (eg, with transfusions of red blood cells or platelets) may be used to relieve symptoms and improve quality of life.

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). For most patients with chronic-phase CML who are treated with TKIs, median survival is expected to approach normal life expectancy. ^{[1, 14]}

The standard treatment of choice for chronic phase CML is a TKI: either the first-generation TKI imatinib, which is a specific small-molecule inhibitor of BCR/ABL in all phases of CML, or a second-generation TKI—nilotinib (Tasigna), dasatinib (Sprycel), or bosutinib (Bosulif). Although the second-generation TKIs 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, 17]} Current National Comprehensive Cancer Network guidelines list imatinib as a preferred agent for low-risk CML and recommend second-generation TKIs as preferred agents for intermediate- and high-risk chronic phase CML. ^[18]

In patients with a durable deep molecular response to TKI therapy, treatment discontinuation may be considered (see Long-Term Monitoring, below). However, only about 20% of patients wich chronic-phase CML achieve treatment- free remission; most patients with CML require lifelong TKI therapy. ^[19] Consequently, drug cost is an important consideration. From 2001, when imatinib was first approved for use in CML, to 2016, when it went off patent, the list price of imatinib in the United States rose from $26,400 per year to $142,000 per year. Second-generation TKIs have demonstrated similar price increases. ^[20]

Once a generic version of imatinib became available, in 2016, costs fell only modestly at first. ^[20] As of December 2018, the average price of generic imatinib in the United States was $35,000/year, while prices of second-generation TKIs were $150,000+/year. Prices in other countries were substantially lower. ^[21]

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 ^[22] 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 Chronic Myelogenous Leukemia Treatment Protocols.

Imatinib 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, 23, 24]}

For patients with chronic-phase CML, imatinib at 400 mg/day is the recommended 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%.

In patients unable to tolerate 400 mg/day of imatinib, the dosage may be reduced to 300 mg/day if the response is optimal. ^{[18, 19]} However, dosages of less than 300 mg/day have been associated with inferior response and survival rates. ^[18]

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 suggested that higher-dose imatinib was not associated with lower rates of disease progression than imatinib at 400 mg, but was associated with higher rates of dose interruption, reduction, or discontinuation due to grade 3 or 4 adverse events. ^[18]

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. ^[25]

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. ^[26]

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. ^[27] The estimated rates of complete cytogenetic response were 76.2% for the imatinib group and 14.5% in the interferon alfa group. ^[27]

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. ^[27]

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. ^[28]

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%. ^[26] 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, 29]}  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. ^{[18, 30]}

Kidney 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 (eGFR). ^[31]

Currently, three second-generation tyrosine kinase inhibitors (TKIs) and two third-generation TKIs are available for treatment of CML. These agents are orally administered, generally well-tolerated, and highly effective.

The second-generation 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 BCR/ABL/T315I. 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 those with chronic-phase CML that is resistant to or who are intolerant of prior therapy that included imatinib. ^{[32, 33, 34]}  Dasatinib and bosutinib are also FDA-approved for accelerated- and blast-phase Ph1⁺ CML in patients resistant to or intolerant of other therapies,  and nilotinib is approved for resistant/intolerant accelerated-phase CML.

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. ^[35]

That said, these new TKIs are not without their drawbacks and adverse events. Dasatinib has been associated with pleural effusions and pulmonary arterial hypertension, ^[36] 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 remains a preferred first-line treatment for low-risk chronic phase CML. ^[18] It is also less expensive than the new TKIs, 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. ^[37] Using the MD Anderson prognostic factors scoring may help in identifying the few patients requiring the more expensive second-generation agents for first-line use. ^[38]

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. ^[39]

The development of BCR/ABL1 TKIs over the past 20 years has dramatically improved the outcomes for patients with every stage of Philadelphia chromosome–positive (Ph+) CML.

How should these agents be used for an individual patient to ensure the best possible duration and quality of life, to avoid treatment-related complications, and potentially to achieve a cure at an affordable cost? Because CML patients may need to continue TKI therapy indefinitely, the long-term safety of each treatment option must be considered. Evidence-based care requires an understanding of the optimal use of these drugs, their specific early and late toxicities, the prognostic significance of achieving treatment milestones, and the critical importance of molecular monitoring.

Equally important determinants for which drug to use for an individual patient include tolerance (because it influences treatment adherence as well as quality-of-life), comorbidities and thus potential late complications, calculated risk status at diagnosis, and the achievement of molecular response.

Although efficacy is important, treatment choice does not depend only on efficacy. Choosing among various treatment options is informed by understanding the distinct benefits and risks of each agent, along with careful consideration of patient-specific factors, such as risk status, age, and comorbidities. Finally, given the high cost of these agents and the need for prolonged—often, lifelong—treatment, financial issues must also be considered.

Tthe choice of initial is likely to be driven by two considerations: one clinical (because survivals with different agents appear equivalent despite differences in efficacy), and the other financial (the price of generic imatinib is likely to fall to 20%-30% of the cost of the branded drug and the second-generation TKIs). Equally important determinants for which drug to use for an individual patient include the following:

• Tolerance (because it influences treatment adherence as well as quality of life)
• Comorbidities (and thus potential late complications)
• Calculated risk status at diagnosis
• Achievement of early molecular response (EMR)

Eventually, gene expression profiling may provide a better way to identify which patients require a second-generation TKI from the outset. The T315I mutation confers complete resistance to imatinib,dasatinib, nilotinib, and bosutinib; the presence of this mutation is an indication for the use of a third-generation TKI, posatinib or asciminib. For now, appropriate monitoring and the use of guidelines regarding when to switch is the key to optimizing outcomes.

Dasatinib

Dasatinib, an inhibitor of multiple tyrosine kinases, received accelerated approval in 2006 for second-line treatment of all phases of CML, and received approval for first-line treatment of chronic-phase CML in 2013. 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. ^[40]

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. ^[41] 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. ^[41]

The efficacy and safety of dasatinib in patients with newly diagnosed Ph1⁺ CML that is in the chronic phase were demonstrated in the DASISION (Dasatinib vs Imatinib Study in Treatment-Naïve CML Patients) study, an ongoing open-label randomized phase III trial. ^[42]  The confirmed cytogenetic response rate (CCyR) was higher in patients treated with dasatinib than with imatinib at 12 months (77% vs 66%, respectively) and at 36 months (83% vs 77%). The rate of major molecular response (MMR) was also higher for dasatinib at both 12 and 36 months.

In CA180‐034, an open-label phase III study of dasatinib in 670 patients with imatinib‐resistant or ‐intolerant CML, 7-year analysis showed MMR of 46%, progression-free survival (PFS) of 42%, and overall survival (OS) of 65% in which transformation from chronic phase to accelerated or blast-phase CML occurred in fewer than 5% of dasatinib patients by 5 years. ^[43]

Nilotinib

Nilotinib received approval for second-line treatment of CML in 2007, and received approval for first-line treatment of chronic-phase CML in 2010. Nilotinib has been found superior to imatinib in patients with newly diagnosed chronic-phase Ph+ CML. ^[44] 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. ^[45]

The FDA has also approved nilotinib for first- and second-line treatment of pediatric patients aged 1 year and older with chronic-phase Ph+ CML. Approval was based on a cohort of 69 pediatric patients with chronic-phase Ph+ CML-CP who were either newly diagnosed or had resistance to or intolerance of TKI treatment. The 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 in MMR; the cumulative MMR rate was 47.7% by cycle 12, and the median time to first MMR was 2.8 months. ^[46]

Bosutinib

After granting accelerated approval in 2017, in 2021 the FDA issued standard approval of bosutinib for newly diagnosed chronic-phase Ph+ CML. Approval was based on the BFORE study, a multinational, phase III study enrolling 536 patients with newly diagnosed chronic-phase CML. Cumulative major molecular response (MMR) by Month 60 in the modified intent-to-treat (mITT) population was 74% (95% CI: 69-80%) in the bosutinib arm and 66% (95% CI: 60-72%) in the imatinib arm. After 60 months of follow-up, the median time to MMR in responders was 9 months for bosutinib and 11.9 months for imatinib. ^{[47, 48]}

Ponatinib

The third-generation TKI ponatinib (Iclusig) was approved by the FDA in 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 second-generation tyrosine kinase inhibitors. ^{[49, 50, 51]}

In the phase II 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). ^{[49, 50, 51]}

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. ^[52] 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. 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 ^[53] :

• 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.      

A German expert consensus panel has published recommendations on management of cardiovascular risk in patients receiving ponatinib. ^[54]

Asciminib

 In 2021, the FDA granted asciminib (Scemblix) accelerated approval for Ph+ CML in chronic phase in adults previously treated with 2 or more TKIs. Asciminib is also fully approved for the treatment of Ph+ CML in chronic phase in adults with the T3151 mutation.

Accelerated approval was granted on the basis of the phase III ASCEMBL trial, in which MMR was nearly twice as high in patients receiving asciminib than in those receiving bosutinib (25% vs 13%). Fewer patients in the asciminib arm discontinued treatment due to adverse reactions compared with those in the bosutinib arm (7% vs. 25%). On longer-term follow-up of ASCEMBL, the MMR rate at week 96 was 37.6% with asciminib vs 15.8% with bosutinib. ^[55]

Full approval of asciminib for treatment of chronic-phase Ph+-CML with T3151 mutation was based on the open-label CABL001X2101 study, in achievement of MMR occurred in 42% of patients by week 24 (19 of 45 patients; 95% CI: 28% to 58%) and in 49% of patients by week 96 (22/45, 95% CI: 34% to 64%). ^[56]

Pemigatinib

Pemigatinib is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3). It inhibits FGFR 1/2/3 phosphorylation and signaling, and decreases cell viability in cancer cell lines that have activating FGFR amplifications and fusions. It is indicated for relapsed or refractory myeloid/lymphoid neoplasms (MLNs) in adults with FGFR1 rearrangement. 

Approval was based on the phase II FIGHT-203 clinical trial. Study participants included patients with documented myeloid/lymphoid neoplasms with an 8p11 translocation on conventional cytogenetics and/or an FGFR1 rearrangement on break-apart fluorescence in situ hybridization (FISH) testing. 

In patients with chronic phase in the marrow, with or without extramedullary disease (EMD) (n = 18), the complete response (CR) rate was 78%. The median time to CR was 104 days (range, 44 to 435 days), and the median duration of CR was not reached. In patients with blast phase in the marrow, with or without EMD, 2 of the 4 patients achieved a CR. For all patients (n = 28, including 3 patients without evidence of morphologic disease) the complete cytogenetic response rate was 79% (95% confidence interval: 59-92%). ^[57]  

The protein translation inhibitor omacetaxine (Synribo) is approved for treatment of chronic- or accelerated-phase CML in patients with resistance to and/or intolerance of 2 or more tyrosine kinase inhibitors (TKIs) (eg, dasatinib, nilotinib, imatinib). Approval was based on combined data from 2 phase II 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. ^[58]

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. ^[30]

Busulfan

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

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.

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 (TKIs), interferon alfa is no longer considered first-line therapy for CML. It may be used in pregnant patients, as fetal harm has been reported with TKI therapy. ^{[18, 19]}

Interferon alfa may also be used in combination with TKIs 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. ^[59]

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. ^{[60, 61]} 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. ^[62]

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 (ie, donor lymphocyte infusion).

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.

Molecular monitoring in CML is a powerful tool to document treatment responses and predict relapse. Nonetheless, the proliferation of clinical trials and guidelines using the molecular endpoints of CML has outpaced practice norms, commercial laboratory application, and reimbursement practices, leaving some clinicians feeling anxiety (if not confusion and despair) about molecular monitoring in the day-to-day treatment of CML. 

Given the power of molecular monitoring in the transplantation setting, which has now been largely displaced by effective TKIs, molecular monitoring was used in the TKI trials as a measure of disease response. Such monitoring is now advocated for the routine clinical care of CML. The cytogenetic response is monitored every 3-6 months. Methods include karyotyping and fluorescence in situ hybridization (FISH) to count the percentage of bone marrow cells that are Ph1 positive. ^[63]  

The most sensitive method for detecting CML is quantitative reverse transcriptase PCR (RT-PCR) for BCR/ABL messenger RNA (mRNA), which can detect one CML cell in approximately 100, 000 to 1 million cells. The assay has well-documented pitfalls, mostly revolving around its complexity and the lack of standardization across laboratories. On an extremely positive note, peripheral blood can be used instead of bone marrow for monitoring, because a good correlation exists between BCR/ABL mRNA in bone marrow and peripheral blood.

Molecular responses are defined by the magnitude of reduction in BCR-ABL transcripts from a standardized value (rather than an individual patient's original level). A major molecular response (MMR) is defined as a more than 3-log reduction in BCR-ABL/control gene ratio. The criteria for monitoring patients receiving TKIs are summarized in the European LeukemiaNet and National Comprehensive Cancer Network (NCCN) guidelines. ^[64]

The goal is 100% normal cells after 1-2 years of therapy. Patients who remain BCR/ABL positive (ie, those with minimal residual disease [MRD]) should be kept on maintenance therapy as long as they continue to have MRD.

Early monitoring after starting TKI therapy may also be useful in predicting response. The rate of BCR-ABL decline in the initial 2 to 3 months of imatinib therapy is a strong predictor of subsequent response, as patients with less than 1-log reduction after 3 months had a 13% probability of ever achieving an MMR after 2.5 years of follow-up, compared with more than 70% in patients with more than 1-log response. ^[65]  

Cortes et al found that patients with chronic phase CML who have a less than 1-log reduction after 3 months of imatinib therapy had a 55% chance of ever achieving a MMR at 2 years, compared with those with a more than 1-log or 2-log reduction, in whom an MMR was achieved in 84% and 95%, respectively. ^[66]  

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).

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; 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.

Transcript increases after complete cytogenetic response

The BCR-ABL PCR result may rise in a patient for a number of reasons. One possibility is decreased compliance, especially in the context of an expensive drug and a patient who has had a good molecular response (a situation where the temptation to enjoy a “drug holiday” is strong). Second, variability in the test itself may result in some increase or decrease, especially when the tumor burden is very low. In most laboratories, however, a 5- to 10-fold change in the PCR result is probably “real.”

However, it is possible that BCR-ABL levels may vary naturally over time in patients on TKI therapy. CML is known to have cyclic oscillations, with peaks and troughs occurring at even 1- to 2-month intervals, and this has not been studied in cases with residual disease. Several lines of evidence suggest that a truly rising BCR-ABL deserves concern. First, several studies have shown that a rising BCR-ABL is associated with a greater increase of the acquisition of an Abl point mutation and resistance. ^[67]  In addition, loss of MMR is associated with an increased risk of relapse and lower disease-free survival. ^[68]  

Nonetheless, not all patients with a rise in BCR-ABL, or a detectable mutation, inevitably relapse. A reasonable first action is to repeat the test (eg, in a month). If the result is still increased (or is increasing), then mutation testing should be undertaken. The next response depends on how high the BCR-ABL level has risen. A rise from the lowest levels of detection (0.0001%) to a value even 50 times higher would still be well with the range of a MMR. However, a patient who begins at the MMR and rises above that level is certainly heading toward cytogenetic relapse, and here a bone marrow aspirate looking for cytogenetic recurrence would be warranted.  

Abl mutations

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.

Quantitative PCR is uniquely sensitive because it is amplifying a chimeric mRNA not found in normal cells. The detection of a single point mutation in the tyrosine kinase domain of BCR-ABL against a background of wild type BCR-ABL is obviously a much more difficult task.

The most common method, direct nucleotide sequencing, can detect an Abl tyrosine kinase domain mutation if it composes 10% to 20% of the total BCR-ABL sampled population. The prevalence of Abl mutations increases with the “disease time”—that is, these mutations are rare in newly diagnosed chronic-phase CML and increase with late chronic-phase and advanced-phase disease (ie, with increasing Sokal score).Thus, Abl mutations occur as part of the natural history of CML, rather than a merely a manifestation of selective pressure from TKI therapy.

Several studies have demonstrated that these mutations are associated with both an increase in loss of cytogenetic response and progression to advanced-phase disease. However, in some cases, particularly in those patients with a low disease burden, mutations can be detected yet remain at a low level and do not cause problems. One should use caution and reason concerning the “2-fold” rule because an increase from a PCR-negative status to a level of 0.0001% would be an infinite increase in BCR-ABL but should not cause much worry.

Thus, screening for mutations would be reasonable in any of the following:

• Patients with advanced-phase CML
• Patients with chronic-phase CML who are not achieving cytogenetic milestones
• Patients with a rising  BCR-ABL level, especially one nearing or passing the MMR level

Testing frequency 

The set guidelines of the European LeukemiaNet and the National Cancer Care Network suggest peripheral blood testing every 3 months for quantitative PCR. On a practical note, however, if a patient has been in an MMR (or, better yet, complete molecular remission) for months, it may be reasonable to extend the testing interval to every 6 months. If a significant change in BCR-ABL level occurs (negative to positive, or a > 2- to 5-fold increase in patients with detectable disease), then resuming more frequent testing is prudent.                                                                                                                             

Discontinuation of TKI therapy

Discontinuing TKI therapy for certain patients, an approach first put forward in 2006, has the potential to reduce side effects associated with lifelong TKI therapy and to be cost-effective measure. Treatment-free remission (TFR) is achieved when a patient who has discontinued TKI therapy maintains an MMR and does not need to restart therapy.

Several guidelines provide recommendations on discontinuation of TKI treatment. European LeukemiaNet guidelines recommend that patients with CML who are responding optimally to treatment continue it indefinitely, but advise that treatment discontinuation may be considered in individual patients, especially women of childbearing age who have achieved an optimal response and are considering pregnancy. ^[19]

European Society for Medical Oncology (ESMO) guidelines advise that treatment discontinuation may be considered in individual patients, provided that proper, high-quality and certified monitoring can be ensured. ^[30]  ESMO prerequisites for safe discontinuation include the following:

• Meeting institutional requirements for safe supervision
• Identification of typical BCR–ABL1 transcripts at diagnosis
• At least 5 years of TKI therapy
• Achievement of MR4.5 (ie, molecular response with 4.5-log reduction)
• Stability of deep molecular remission (at least MR4) for at least 2 years 

NCCN guidelines state that discontinuation of TKI therapy appears to be safe in select CML patients, but recommend consultation with a CML specialist to review the appropriateness for TKI discontinuation and potential risks and benefits, and advise that some patients have experienced significant adverse events that are believed to be due to TKI discontinuation. ^[18]  NCCN criteria for discontinuation are as follows:

• Age ≥18 years.
• Chronic phase CML, with no prior history of accelerated or blast phase CML
• On approved TKI therapy for at least 3 years.
• Prior evidence of quantifiable BCR-ABL1 transcript
• Stable molecular response (MR4; BCR-ABL1 ≤0.01% IS) for ≥2 years, as documented on at least 4 tests, performed at least 3 months apart.
• Access to a reliable quantitative PCR test with a sensitivity of detection of at least MR4.5 ( BCR-ABL1 ≤0.0032% International Scale [IS])

For monitoring after TKI discontinuation, the NCCN recommends monthly molecular monitoring for 1 year, then every 2 months for the second year, and every 3 months thereafter (indefinitely) in patients who remain in MMR (MR3; BCR-ABL1 ≤0.1% IS) 

The NCCN recommends prompt resumption of TKI within 4 weeks of a loss of MMR, monthly molecular monitoring until MMR is re-established, then every 3 months thereafter, indefinitely. In patients who fail to achieve MMR after 3 months of TKI resumption, BCR-ABL1 kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for another 6 months. ^[18]

In general, patients in the chronic phase of CML with a stable, prolonged, and deep molecular response (DMR) for ≥2 years might be ready to discontinue TKI therapy. ^{[69, 70, 18, 71]}

Patients who have achieved an MMR/MR but have not reached a DMR and are therefore not eligible to attempt TFR should be reassured by their physicians that they have still reached a treatment goal or safe haven and can continue receiving TKI treatment and have a similar life expectancy to that of the general population. If these patients continue to adhere to treatment they may in time reach a deeper molecular response, at which point, once sustained, TFR might be an option.

If a patient wishes to stop treatment because of problems with the TKI, the physician should discuss with the patient the possibility of switching to a second-generation TKI that might enable achievement of a deeper molecular response. At this time, the patient should be advised about the adverse-effect profiles of TKI treatments. 

Before discontinuing TKI therapy, the physician needs to confirm that the patient understands the need to attend more-frequent routine clinic visits (eg, montlhly for the first year) and undergo regular and lifelong monitoring. TFR does not mean a cure, and molecular recurrence can develop at any time, requiring TKI treatment to be restarted. Clinical monitoring will also enable the identification of long-term toxicity of previous TKI therapy. 

The treating physician should discuss TKI withdrawal syndrome with patients thinking about discontinuing TKI therapy. TKI withdrawal syndrome is seen in up to 30% of patients and can last for months. The syndrome consists principally of musculoskeletal pain. Generally, the pain can be managed with over-the-counter pain medications such as acetaminophen or nonsteroidal anti-inflammatory drugs. In more severe cases, corticosteroids may be indicated.

TKI withdrawal syndrome does not appear to be dependent on the particular TKI the patient was taking, and its occurrence has been associated with a greater chance of achieving successful TFR.

Screening for potential psychological issues associated with TFR should form a part of routine monitoring, because certain patients may require professional psychological help. Physicians should also be aware that patients could experience anxiety as a result of fluctuating BCR-ABL blood levels during TFR. The main anxiety that patients have experienced is a fear of disease recurrence or progression.

About 82% of patients would be willing to stop TKI therapy if their disease were likely to remain stable and, if treatment needed to be restarted, the probability of a response to TKI therapy were high. ^[69] Patients were also more likely to attempt TFR if their risk of recurrence was < 30%; in fact, 40% to 60% of patients sustain TFR for longer than 1 to 2 years. Most cases of molecular recurrence will develop within the first 6 months of stopping TKI therapy, and the confirmed loss of MMR should be seen as an indication to restart therapy. Late molecular recurrences do develop; thus, patient adherence to monitoring during TFR is vital to detect recurrence and ensure protection from disease progression.  

Factors that are potentially predictive of molecular recurrence include previous TKI treatment duration and previous duration of DMR. Studies have shown that resuming TKI therapy immediately after the loss of MMR results in regaining MMR in almost all patients. No risk, to date, has been found of developing resistance to TKIs, and attempting a second TKI discontinuation after molecular recurrence is possible, once a prolonged DMR has again been achieved. Some data have shown this might be effective in ∼30% of cases after an adequate duration of the re-achieved DMR. The speed of molecular recurrence after the first attempt at TFR was the only factor associated with a poorer outcome with the second attempt.  

Worldwide, more than 2000 patients with CML have attempted TFR, and no instances of disease progression have been reported. Attempting TFR may become a standard part of CML care, and with patients’ concerns addressed in patient–physician discussions, a greater number of eligible patients will be willing to discontinue TKI therapy and attempt TFR outside a clinical trial.