Chronic Myelogenous Leukemia Treatment Protocols 

Updated: May 26, 2017
  • Author: Rossa Khalaf, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment Protocols

Treatment protocols for chronic myelogenous leukemia (CML) are provided below for chronic phase, accelerated phase, and blast phase.

General treatment recommendations for chronic myelogenous leukemia

Tyrosine kinase inhibitors (TKIs) are the drugs of choice for initial therapy of CML. [1] Imatinib was the first oral TKI approved for treatment of CML, in May 2001. Subsequently, second- and third-generation of TKIs (eg, dasatinib, nilotinib) were approved for first-line therapy. [2, 3]  

Treatment with TKIs significantly decreases the mortality rate in patients with CML. A study by Tang et al determined that long-term TKI therapy may reduce the abundance of leukemic stem cells in select patients. [4] A study by Gugliotta et al that examined the use of imatinib in patients aged 65 years or older found that the response to imatinib was not affected by age. [5]

In the IRIS (International Randomized Study of Interferon and STI571) study, imatinib produced a higher rate of complete cytogenetic response (CCyR) and major cytogenetic response (MCyR) compared with interferon alpha and cytarabinenal. [6] Additionally, a follow-up study showed significant improvement in 8-year event survival, freedom from progression to accelerated phase or blast phase, and overall survival. [7]

Several studies have evaluated the efficacy and safety of higher doses of imatinib (800 mg daily) in newly diagnosed chronic-phase CML (CP-CML). [7, 8, 9] In the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study, higher and faster CCyR and major molecular response (MMR) were noted early on with 800 mg versus 400 mg of imatinib, but no difference in response rates at 12 month and beyond was found. [9]

In the IRIS (International Randomized Study of Interferon and STI571) study, imatinib produced a higher rate of complete cytogenetic response (CCyR) and major cytogenetic response (MCyR) compared with interferon alpha and cytarabinenal. [6] Additionally, an 8-year follow-up study showed significant improvement in 8-year event survival, freedom from progression to accelerated phase or blast phase, and overall survival. [7]

Several studies have evaluated the efficacy and safety of higher doses of matinib (800 mg) in newly diagnosed CP-CML [7, 8, 9] In the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study, patients who had fewer treatment interruptions and who received higher imatinib doses had higher and faster response rates in the first year of treatment, but by 42 months the high- and low-dose arms showed similar rates of major molecular response (MMR) and no differences in event-free survival (EFS), progression-free survival (PFS), or overall survival (OS) [9]

The CML-IV and SWOG 0325 studies reported higher rates of MMR with 800 mg of imatinib at 12 months; however, the higher dose was not associated with lower rate of progression to an advanced stage of CML. Also, grade III and IV adverse events and higher rates of interruptions, dose reduction, and even discontinuation were noted. [10]

The second-generation TKIs have shown superior efficacy and higher rates of CCyR and MMR when compared with imatinib. Lower rates of transformation to advanced phase were also seen. [2, 3]

In the DASISION (DASatinib versus Imatinib Study In treatment-Naive CML patients) trial, final 5-year analysis showed significantly higher MMR and molecular response with ≥4.5 log reduction of BCR-ABL on the International Scale (MR4.5) in patients with newly diagnosed CP-CML who received dasatinib, 100 mg once daily (n = 259), than in those who received imatinib, 400 mg once daily (n = 260). However, the estimated 5-year PFS and OS were similar in both groups. [2]

In the ENESTnd trial, which compared nilotinib with imatinib in patients with newly diagnosed CP-CML, by 5 years, more than half of all patients in the nilotinib arm achieved an MR(4.5) compared with less than a third of patients in the imatinib arm. In addition, patients receiving nilotinib demonstrated a lower rate of progression to the accelerated or blast stage of CML. Also in this study, the 5-year OS and PFS were similar in both groups. [3]

In patients who receive first-line therapy with TKIs, the rate of decline in BCR-ABL1 transcripts correlates with long-term response. [11, 12] The IRIS investigators reported that patients with BCR-ABL transcripts of >10% at 6 months and >1% at 12 months had inferior EFS and higher rate of progression to accelerated- or blast-phase CML, while those with an MMR (BCR-ABL1 ≤ 0.1%) by 18 months had no progression to advanced disease and 95% EFS at 7 years. Early cytogenetic response or molecular response to second-line and subsequent TKI therapy have also been found to be good predictors of OS and PFS. [13, 14, 15]

Chronic phase treatment recommendations

For CP-CML, determination of the patient's Sokal or Hasford risk score is recommended prior to initiation of TKIs. The Sokal score is based on the patient’s age, spleen size, peripheral platelet count, and blast percentage in peripheral blood, while the Hasford score is based on peripheral eosinophil and basophil counts in addition to the Sokal parameters. Either of these scores helps in stratifying patients with CP-CML into low, intermediate, or high risk, which will guide the choice of TKI. [16, 17] In addition to the risk score, the toxicity profile of theTKI and patient comorbidities guide the choice of therapy.

For low-risk patients, any of the following may be used for first-line treatment [2, 3, 15, 18] :

For intermediate- or high-risk patients, dasatinib or nilotinib is preferred over imatinib; dosages are the same as for low-risk patients. [2, 3, 15, 18] Note that allogeneic hematopoietic stem cell transplantation (HCT) is not recommended as first-line treatment for CP-CML.

For the rare patient who is intolerant to those TIKIs, consider one of the following (note that bosutinib and ponatinib are approved for use only patients resistant to or intolerant to other therapies, not for first-line treatment):

For patients with intolerance to all TKIs , the following options can be alternatives:

Supportive therapy

For symptomatic leukocytosis, options include the following:

For symptomatic thrombocytosis, options include the following:

  • Hydroxyurea
  • Anti-aggregants
  • Apheresis

Resistance or intolerance to TKIs

Response to TKI is monitored. If desired milestones are not achieved, evaluation for patient compliance, consideration of a new drug interaction, and mutation analysis are recommended. If intolerance or inadequate response is confirmed, the treatment options are based on the first-line TKI that was used, as follows:

  • If there is intolerance or inadequate response to imatinib, other TKIs that can be used are dasatinib, nilotinib, or bosutinib.
  • If there is intolerance or inadequate response to dasatinib, other TKIs that can be used are nilotinib or bosutinib.
  • If there is intolerance or inadequate response to nilotinib, other TKI options are dasatinib or bosutinib

The risk of progression is high after failure of dasatinib or nilotinib, and no clear evidence suggests that switching to different TKI in such cases will improve long-term outcomes. [19] Options include the following:

Omacetaxine

Omacetaxine (Synribo) is a protein translation inhibitor that is indicated for chronic- or accelerated-phase CML with resistance and/or intolerance to two or more TKIs (eg, dasatinib, nilotinib, imatinib). [20, 21] Regimens are as follows:

  • Induction: 1.25 mg/m 2 SC twice daily for 14 consecutive days of a 28-day treatment cycle; repeat cycles until hematologic response is achieved
  •  Maintenance: 1.25 mg/m 2 SC twice daily for 7 consecutive days q 28 days; continue as long as clinically beneficial

Ponatinib

Ponatinib (Iclusig), a pan–BCR-ABL TKI, is approved for patients with any phase of CML (chronic, accelerated, blast) that is resistant or intolerant to prior TKI therapy, including those with the T315I mutation. [22] Because ponatinib poses a high risk for thromboembolic events, its use is restricted to patients for whom no other TKI therapy is indicated. [19]

Ponatinib dose: 45 mg PO daily; continue as long as there is no evidence of disease progression; dosage reduction recommended for coadministration with CYP3A4 inhibitors and toxicities

Bosutinib

Bosutinib (Bosulif), a second-generation TKI,  is a dual Src and ABL kinase inhibitor. It is approved for chronic-, accelerated-, or blast-phase Ph+ CML in patients resistant to or intolerant of other therapies, including imatinib, dasatinib, or nilotinib, but is not for use in cases with the T315I mutation. [23]

Bosutinib dose: 500 mg once daily with food; if complete hematologic response (CHR) is not achieved by by week 8 or CCyR by week 12, increase the dose to 600 mg once daily if no toxicity is identified

Monitoring response to TKI therapy

Response to TKI is usually monitored by measurement of hematologic, cytogenetic, and molecular responses. [24, 25, 26]

Complete hematologic response

CHR is defined by the following:

  • Normalization of blood count, with white blood cell count <10,000/μL and platelet count <450,000/μL
  • Normal peripheral blood smear with no immature cells (eg, promyelocytes, myelocytes, blasts)
  • Absence of disease symptoms and palpable splenomegaly

Cytogenetic response

Cytogenetic response is usually done on bone marrow samples in metaphase (at the time of diagnosis and if failure to achieve desired milestones or loss of milestones occurs) and is defined as follows [19] :

  • Complete cytogenetic response (CCyR): Absence of Philadelphia chromosome–positive (Ph+) cells in metaphase
  • Partial cytogenetic response (PCyR): Presence of Ph+ cells in 1%-35% metaphases
  • Major cytogenetic response: Presence of Ph+ cells in 0%-35% metaphases
  • Minor cytogenetic response: Ph+ >35% metaphases

Molecular response

Molecular response is monitored by quantitative polymerase chain reaction (qPCR) studies on peripheral blood. It is usually performed at diagnosis, then every 3 months until BCR-ABL1 transcripts are <0.1%, then every 3-6 months. Definitions are as follows:

  • Early molecular response: BCR-ABL1 transcripts ≤10% at 3 and 6 months after TKI initiation
  • Major molecular response: BCR-ABL1 transcripts <0.10%
  • Deep molecular response: No detectable BCR-ABL1 transcripts

According to the National Comprehensive Cancer Network (NCCN), the response milestones that should be achieved are the following [19] :

  • BCR-ABL1 transcripts of 1%-10% at 3 or 6 months
  • BCR-ABL1 transcripts of 0.1% to <1% at 12 months
  • BCR-ABL1 transcripts <0.1% after 12 months

QPCR has high sensitivity and correlates strongly with the results obtained from bone marrow studies, so it can obviate bone marrow biopsy during treatment. [27] However, if qPCR is not available, then treatment monitoring should use bone marrow cytogenetics. [25, 26]

In patients with lack of CHR, or whose cytogenetic response had shown 100% Ph+, results of cytogenetic response measured at 3-months, and recommended treatment strategies, are as follows [19] :

  • Ph+  >65%: Switch to different TKI, clinical trial enrollment, or evaluate for HCT
  • Ph+ ≤65%: Continue TKI at same dose

In patients who had 36%-95% Ph+, results of cytogenetic response measured at 3 months, and recommended treatment strategies, are as follows [19] :

  • Ph+ >35%: Switch to different TKI, clinical trial enrollment, or evaluate for HCT
  • Ph+ ≤35%: Continue TKI at same dose

In patients who had 1%-35% Ph+, results of cytogenetic response measured at 3-months, and recommended treatment strategies, are as follows [19] :

  • Ph+ >0%: Switch to different TKI, clinical trial enrollment, or evaluate for HCT
  • Ph+ 0%: Continue TKI at same dose

 At 12 months, if Ph + >35%, then treatment options are to switch to a different TKI, enroll the patient in a clinical trial, or evaluate for HCT. If Ph + <35%, continue the TKI at the same dose. Monitor for toxicity.

Bone marrow cytogenetics should be repeated if milestones are not achieved or any loss of response to treatment occurs. QPCR should be done in 1-3 months when there is a 1-log increase in BCR-ABL1 transcripts with MMR. Mutation analysis should be done if there is a 1-log increase in BCR-ABL1 transcripts without MMR. If none of the cytogenetic or molecular milestones are achieved at 3, 6, or 12 months after second-line and subsequent TKI therapy, then alternative therapies or allogeneic HCT are recommended.

Accelerated- and blast-phase CML

Clinical trials should be recommended to all patients with acclerated-phase CML (AP-CML) and blast-phase CML (BP-CML). Mutation analysis is recommended for all patients with advanced disease prior to initiation of TKI therapy. Patients whose CML progresses to an advanced phase while on TKI therapy have a worse prognosis than those with de novo advanced-phase CML.

Accelerated-phase CML

  • TKIs are recommended as first-line treatment for patients with newly diagnosed AP-CML
  • In patients with disease progression to AP-CML while on TKI therapy, an alternate TKI will be beneficial as a bridge to allogeneic HCT
  • Omacetaxine is an option for patients with disease progression to AP-CML on TKI therapy

Blast-phase CML

Initial presentation with BP-CML is rare. Allogeneic HCT is recommended as the first-line treatment in these cases. However, patients who progressn to BP-CML while on TKI therapy, should be switched to an alternate TKI as a bridge therapy before allogeneic HCT.

TKI along with induction chemo therapy are indicated. AML induction therapy to be used when myeloid BP-CML and ALL induction therapy is recommended in lymphoid BP-CML.

CNS prophylaxis is recommended for lymphoid type as CNS involvement was reported (30)

The risk of relapse is high and treatment options include Donor Lymphocyte infusion (DLI), Imatinib in patients who didn’t fail Imatinib initially, or combined DLI along with Imatinib

Dasatinib may be effective for treatment of extramedullary relapse following transplant (31)

TKI doses for advanced-stage disease

TKI doses recommended for AP-CML and BP-CML are as follows:

  • Imatinib – 300 mg twice a day or 600 mg once daily
  • Nilotinib – 400 mg twice a day
  • Dasatinib – 140 mg daily
  • Ponatinib – 45 mg once daily
  • Omacetaxine dosing for AP-CML is the same as for CP-CML; omacetaxine is not used in BP-CML

Discontinuation of TKI therapy

Several studies have demonstrated that discontinuation of TKI therapy is feasible in very carefully selected patients, after the desired response has been achieved and BCR-ABL1 transcripts have become clinically undetectable. Approximately 40%-60% of those patients relapse within 6 months, but typically, all patients who have relapsed respond to resumption of TKI therapy. [28, 29, 30] However, discontinuation of TKIs is associated with significant adverse events (eg, musculoskeletal pain) in some patients. [30, 19]

33 Resumptions of treatment immediately after recurrence occurred, achieved undetectable minimal residual disease similar results were also reported for other TKI therapy .However very strict criteria were used and if discontinuation of TKI wanted, then all these criteria should be met and meticulous follow up recommended34 

The National Comprehensive Cancer Network (NCCN) lists the following criteria for discontinuing TKI therapy:

  • Age ≥18 years
  • CP- CML
  • No prior history of AP-CML or BP-CML
  • On approved TKI therapy (imatinib, dasatinib, nilotinib, bosutinib, or ponatinib) for at least 3 years.
  • Prior evidence of quantifiable BCR-ABL1 transcript.
  • Stable molecular response (MR4; ≤0.01% International Scale [IS]) for ≥2 years, as documented on at least four tests, performed at least 3 months apart.
  • No history of resistance to any TKI.
  • Access to a reliable QPCR test with a sensitivity of detection of ≥4.5 logs that reports results on the IS and provides results within 2 weeks.
  • Monthly molecular monitoring for the first 6 months following discontinuation, bimonthly during months 7–24, and quarterly thereafter (indefinitely) for patients who remain in MMR (MR3; ≤0.1% IS).
  • Consultation with a CML Specialty Center to review the appropriateness for TKI discontinuation and potential risks and benefits of treatment discontinuation, including TKI withdrawal syndrome.

For patients who lose MMR, the NCCN recommends prompt resumption of TKI therapy, with monthly molecular monitoring for the first 6 months and every 3 months thereafter, indefinitely. For those who fail to achieve MMR after 6 months of TKI resumption, BCR-ABL1 kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for another 6 months. [19]