Chronic Myelogenous Leukemia Treatment Protocols 

Updated: Jan 11, 2015
  • Author: Kanishka Chakraborty, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment Protocols

Treatment protocols for chronic myelogenous leukemia are provided below for chronic phase, accelerated phase, and blast phase. [1]

See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, to help detect chronic leukemias and determine the specific type present.

General treatment recommendations for chronic myelogenous leukemia

Tyrosine kinase inhibitors (TKIs) are the initial treatment of choice for most chronic myelogenous leukemia (CML) patients [2, 3, 22]

Imatinib is one of the first TKIs approved for patients with chronic myelogenous leukemia; second-generation TKIs have shown greater efficacy and response compared to imatinib. A study by Tang et al has determined that long-term TKI therapy may reduce the abundance of leukemic stem cells in select patients. [4] A study by Gugliotta et al examined the use of imatinib in patients aged 65 years or older and found that the response to imatinib was not affected by age. [7]

Compared with imatinib, the second-generation TKIs nilotinib and dasatinib produce significantly higher rates of major molecular response (MMR) and complete cytogenetic response (CCyR), as well as lower rates of disease progression. [5, 6]

Higher-dose imatinib (600 or 800 mg), if tolerated well, was shown to result in faster and higher CCyR and MMR early on, but no difference in response rates was evident at 12 months [18, 19, 20, 21] . However, the TIDEL study showed better MMR at 12 and 24 months. The German CML IV study also confirmed similar data. [23, 24, 25, 26]

Early response to TKI treatment suggests a more favorable prognosis. [32] An 8-year followup report on the International Randomized Study of Interferon Vs STI571 (IRIS) confirmed that in patients treated with imatinib, minor to partial CyR at 3 months and partial CyR at 6 and 12 months predicted a likelihood of achieving a stable CCyR [31]

The DASISION study (DASatinib versus Imatinib Study In treatment-Naive CML patients) showed similar results: achieving major CyR by 3 or 6 months was a better predictor of PFS after initial treatment with first-line dasatinib in chronic-phase CML. [37] Long-term followup data from IRIS that showed probability of loss of CCyR was only 3% for patients with MMR at 18 months compared with 26% for patients without MMR. [33]

Even in the second-line setting, molecular response at 3 months is a predictor of better overall survival (OS) and event-free survival (EFS) in patients with chronic-phase CML resistant to imatinib [34] .

A study by Costa et al found a potential use for the hypomethylating drug azacitidine in CML, although further research is needed. [8]

Supportive measures

The following supportive measures may be considered [30] :

  • For leukocytosis - Hydroxyurea, leukapheresis
  • For thrombocytosis - Hydroxyurea, anagrelide, apheresis (depending on age and thromboembolic risk)
  • For prevention of tumor lysis syndrome complications - Allopurinol

Chronic phase treatment recommendations

Initial treatment for chronic-phase CML can be with any of the following [1, 5, 6, 9, 10, 11, 12, 13, 14, 15] :

Chronic phase (in patients intolerant to dasatinib, nilotinib, or imatinib)

Consider one of the following for the rare occurrence of intolerance to initial treatment options (note: bosutinib and ponatinib are not FDA-approved for first-line treatment)

At follow-up, if desired responses are not achieved, evaluate patient compliance, consider mutational analysis, and consider one of the following changes, based on the agent used for initial treatment [30] :

  • If imatinib, nilotinib, or dasatinib was used, consider changing to an alternative TKI other than imatinib (eg, dasatinib, nilotinib, bosutinib, or ponatinib)
  • If imatinib was used, consider increasing the dose of imatinib to a maximum of 800 mg as tolerated (if the patient is not a candidate for an alternative TKI)
  • If the patient is unable to tolerate TKI therapy, consider allogeneic HSCT, enrollment in a clinical trial, or interferon/PEG-interferon
  • If resistance and/or intolerance to two or more TKIs occurs, consider omacetaxine (see “Resistance or intolerance to TKIs”)

Accelerated and blast phase treatment recommendations

Treatment for accelerated or blast phase CML can be with any of the following TKIs [16, 12, 13, 30] :

  • Dasatinib 140 mg once daily or
  • Nilotinib 400 mg twice daily or
  • Imatinib 600-800 mg PO once daily or
  • Bosutinib 500 mg PO once daily or
  • Ponatinib 45 mg PO once daily for whom no other TKI therapy is indicated

There is a high relapse rate in patients in accelerated phase even after successful treatment. HSCT should be considered in such cases.

Blast phase treatment resistance or relapse

Patients in the blast phase tend to be relatively resistant to most forms of treatment, [18] and there is a high relapse rate in patients in blast crisis even after successful treatment; HSCT should be considered in these patients. Other options are as follows:

  • Patients in lymphoid blast phase can be treated with acute lymphoblastic leukemia (ALL) induction chemotherapy regimens in combination with a TKI
  • Patients in myeloid blast crisis can be treated with acute myeloid leukemia (AML) induction chemotherapy regimens in combination with a TKI; some patients can be treated with a TKI alone [30]

Resistance or intolerance to TKIs

Options in cases of TKI resistance or intolerance include use of bosutinib, ponatinib, or omacetaxine.

Bosutinib

Bosutinib (Bosulif), a second-generation TKI, is approved for chronic-, accelerated-, or blast-phase Ph+ CML in patients resistant to or intolerant of other therapies, including imatinib. Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines, but did not inhibit T315I and V299L mutant cells.

Bosutinib dose: 500 mg PO once daily with food. The dose may be increased to 600 mg once daily if complete hematological response not achieved by week 8 or a complete cytogenetic response by week 12.

Ponatinib

Ponatinib (Iclusig), a kinase inhibitor, 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. [13] 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 adjustment required for coadministration with strong CYP3A4 inhibitors and toxicities

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] Regimens are as follows:

  • Omacetaxine induction: 1.25 mg/m 2 SC bid for 14 consecutive days q 28 days; repeat q 28 days until hematologic response achieved
  • Omacetaxine maintenance: 1.25 mg/m 2 SC bid for 7 consecutive days q 28 days; continue as long as clinically beneficial

Monitoring of treatment

Patients receiving TKI therapy should be monitored for cytogenetic response every 3 mo, with measurement of BCR-ABL transcript levels in peripheral blood, using quantitative polymerase chain reaction (PCR) and/or fluorescent in situ hybridization (FISH), or assessment of bone marrow. Cytogenetic response is based on presence of Philadelphia chromosome (in metaphase). Assessment in bone marrow at diagnosis and at least 1 year from diagnosis will help to find any other cytogenetic abnormalities.

If assessment at 3 mo shows that BCR/ABL1 transcripts are 10% or less at 3 and 6 mo, the patient is continued on the same dose of the TKI. If analysis at 3, 6, or 12 mo shows inadequate cytogenetic response (eg, BCR/ABL1 transcripts > 10%), further evaluation is required, starting with review of patient compliance and possible drug-drug interactions. [30]

If BCR-ABL transcripts are rising (1 log increase from baseline) with an MMR, repeat evaluation in 1-3 mo; if levels are rising (1 log increase) without an MMR, perform bone marrow cytogenetic analysis; consider mutation testing. [30, 35, 36] If the patient is not in complete cytogenetic remission at 1 y, bone marrow cytogenetic analysis may be needed at 18 mo.

Criteria for responses

A complete hematologic response includes the following:

  • Complete normalization of peripheral blood counts, with a leukocyte count < 10 × 10 9/L and a platelet count < 450 × 10 9/L
  • No immature cells (eg, myelocytes, promyelocytes, or blasts) in the peripheral blood
  • No signs and symptoms of disease; disappearance of palpable splenomegaly

A partial hematologic response is indicated by one or more of the following:

  • Immature cells in the peripheral blood
  • Platelet count < 50% of the pretreatment count but > 450 × 10 9/L
  • Persistent splenomegaly, but < 50% of the pretreatment extent

A complete cytogenetic response requires that there be no Ph+ metaphases. A partial cytogenetic response includes 1-35% Ph+ metaphases

A complete molecular response requires that BCR-ABL mRNA be undetectable by reverse transcriptase polymerase chain reaction (RT-PCR). A major molecular response includes ≥ 3 log reduction of BCR-ABL mRNA [17]

A significant number of patients with chronic-phase CML experience interruptions of imatinib therapy due to nonadherence, which compromises event-free survival. Adherence to therapy is an important evaluation parameter [21]