Chronic myelogenous leukemia medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2]

Overview

Medical therapies for chronic myelogenous leukemia (CML) include chemotherapy, stem cell transplant , and/or biological therapy. With improved understanding of the nature of the bcr-abl protein and its action as a tyrosine kinase, targeted therapies have been developed (the first of which was imatinib mesylate) which specifically inhibit the activity of theBCR-ABL protein. These tyrosine kinase inhibitors can induce complete remissions in chronic myelogenous leukemia, confirming the central importance of BCR-ABL as the cause of chronic myelogenous leukemia.

Until a little more than a decade ago, drug therapy for CML was limited to nonspecific agents such as busulfan, hydroxyurea, and interferon alfa (INF-a) [10]. INF-a led to regression of the disease and improved survival but was hindered by a multitude of toxicities. Allogeneic stem cell transplantation (AlloSCT) was a curative intervention, but carried with it a high risk of morbidity and mortality. Further, alloSCT is only an option for patients with excellent performance status and an appropriate stem cell donor. The landscape changed dramatically with the development of small molecule tyrosine kinase inhibitors (TKIs) that was shown to potently interfere with the interaction between the BCR-ABL protein and adenosine triphosphate (ATP), blocking cellular proliferation of the malignant clone[4]. This “targeted” approach was found to dramatically alter the natural history of the disease, improving 10-year overall survival (OS) from 20 to 80–90% [1,11]. In this review, we will briefly highlight the evidence supporting the use of each of the available TKIs, including how to select an agent in various circumstances and phases of the disease. AlloSCT is performed rarely in CML, and patients who may benefit from such an intervention will be discussed. Cytogenetic and molecular benchmarks for patients on therapy will be mentioned throughout the article. Finally, appropriate monitoring strategies for patients on the various TKIs will be covered. PMID:24729196

Imatinib

Imatinib mesylate (Gleevec, Novartis Pharmaceutical Corporation,NJ), was the first TKI to receive approval by the Food and Drug Administration for the treatment of patients with CML-CP. It acts via competitive inhibition at the ATP-binding site of the BCR-ABL protein, which results in the inhibition of phosphorylation of proteins involved in cell signal transduction. It efficiently inhibits the BCR-ABL kinase, but also blocks the platelet-derived growth factor receptor, as well as the C-KIT tyrosine kinase [15]. The International Randomized Study of Interferon and STI571 (IRIS) study is considered a landmark clinical trial for TKIs and CML [16]. Investigators randomized 1,106 patients to receive imatinib

400 mg/day or INF-a plus low-dose subcutaneous cytarabine. After a median follow-up of 19 months, relevant outcomes for patients receiving imatinib were significantly better than in those treated with INF-a plus cytarabine, notably the rate of complete cytogenetic response (CCyR) rate (74 vs. 9%, P < 0.001), and freedom from progression to AP or BP at 12 months (99 vs. 93%, P < 0.001). Further highlighting the challenge of using IFN-a was the high crossover rate imatinib due to intolerance. The responses to imatinib were also durable, as shown in an 8-year follow up of the IRIS study [11]. Estimated event free survival rate was 81%, and OS rate was 93% when only CML-related deaths were considered. While the results using imatinib are quite impressive, only 55% of patients enrolled in the IRIS study remained on therapy at the 8-year follow up point. This underscored the need for additional options for patients who had failed or were intolerant to imatinib. This led to the rational development of second generation TKIs with hopes they would effectively treat patients unable to continue on imatinib therapy.

Dasatinib

Dasatinib (Sprycel, Bristol-Myers Squibb) is an oral, second generation TKI that is 350 times more potent than imatinib in vitro [17–19]. In addition, it also is known to inhibit the Src family of kinases, which may also be important in blunting critical cell signaling pathways [20]. Though initially evaluated in patients in the salvage setting, clinicians and researchers were excited to test the possibility that frontline use of the more potent inhibitors might further improve the outcome compared to imatinib. The DASISION trial was a phase III, randomized study comparing imatinib 400 mg once daily to dasatinib 100 mg once daily in newly diagnosed patients [21]. Dose escalations were allowed for both drugs in the setting of suboptimal response as defined per protocol. The primary outcome was confirmed cCCyR at 12 months. A total of 519 patients were randomized in a 1:1 manner. Patients assigned to dasatinib achieved cCCyR at 12 months more frequently than those on imatinib (77 vs. 66%, P 5 0.007). Many of the secondary endpoints of interest were also significantly different between groups favoring the dasatinib arm. A three-year follow up of the trial was recently published, and illustrated that dasatinib induces more rapid, deeper responses at early time points compared to imatinib [22]. For instance, at 3 months, a higher proportion of patients treated with dasatinib achieved a BCR-ABL transcript level of less than or equal to 10% (84 vs. 64%, P < 0.0001). Meeting this threshold in either arm predicted for both progression-free survival and OS. As might be expected, pleural effusions occurred more frequently in the group receiving dasatinib (19 vs. < 1%).

Medical Therapy

Medical therapy depends on the phase of chronic myelogenous leukemia.

Chronic Phase

• Targeted therapy

• Targeted therapy is the primary treatment for most people with chronic myelogenous leukemia in the chronic phase. The types of targeted therapy used are:

• Imatinib

• Standard first-line therapy

• Dasatinib

• May be given as a first-line therapy
• May also be used if a person cannot tolerate imatinib or the CML is resistant to imatinib

• Nilotinib

• May be given as a first-line therapy
• May also be used if a person cannot tolerate imatinib or the CML is resistant to imatinib

• Stem cell transplant

• Stem cell transplant may be offered for CML in the chronic phrase.
• It is sometimes used as a primary treatment option for younger people who have an HLA-matched donor.
• It is a treatment option for some people who do not achieve a complete response, develop resistance to or relapse with imatinib.
• A reduced-intensity transplant may be an option for older people who may not tolerate a standard transplant.

• The chemotherapy or radiation used to prepare for a stem cell transplant is less intense than that used for a standard allogeneic transplant.

• Biological therapy

• Biological therapy may be offered for chronic stage CML. Biological therapy can be used alone or in combination with chemotherapy.
• The most common biological therapy used is interferon alfa (Intron A, Roferon A).
• Interferon alfa may be used for people who cannot tolerate, or whose CML is resistant to, imatinib.

• Chemotherapy

• Chemotherapy may be offered for CML in the chronic phase. The types of chemotherapy used are:
• Hydroxyurea (Hydrea, Apo-hydroxyurea, Gen-hydroxyurea)
• Cytarabine (Cytosar)

• May be used in combination with interferon alfa

• Busulfan (Myleran [oral], Busulfex [intravenous])

Accelerated Phase

• Stem cell transplant

• Allogeneic transplant.
• Clinicians usually prefer that the leukemia returns to the chronic phase or is controlled before the transplant.
• Sometimes an autologous transplant.
• A reduced-intensity transplant may be an option for older people who may not tolerate a standard transplant.

• The chemotherapy or radiation used to prepare for a stem cell transplant is less intense than that used for a standard allogeneic transplant.

• Targeted therapy

• Targeted therapy with a tyrosine kinase inhibitor may be offered during the accelerated phase of CML. For those already taking targeted therapy, the dose may be increased. The types of targeted therapy used are:

• Imatinib
• Dasatinib

• Biological therapy

• Interferon alfa
• Cytarabine

• Chemotherapy

• Chemotherapy may be offered for CML in the accelerated phase. The types of chemotherapy used are:

• Cytarabine
• HDAC (high-dose cytarabine)
• Hydroxyurea
• Busulfan
• Busulfex

Blast Phase

• Targeted therapy

• Targeted therapy with a tyrosine kinase inhibitor may be offered for CML in the blast phase. For those already taking targeted therapy, the dose may be increased. The types of targeted therapy used are:

• Imatinib
• Dasatinib

• Chemotherapy

• The most common drugs used when the leukemia cells look like AML include:

• Cytarabine
• HDAC (high-dose cytarabine)
• An anthracycline, such as daunorubicin or doxorubicin
• Tُhioguanine
• Hydroxyurea

• The most common drugs used when the leukemia cells look like ALL include the drugs listed above as well as:

• Vincristine
• Prednisone
• Methotrexate

• There is increased risk of spread to the central nervous system (CNS) during the blast phase, so the following chemotherapy drugs may be given into the spinal fluid (intrathecal):

• Cytarabine
• Methotrexate

• Stem cell transplant

• Allogeneic stem cell transplant

• Radiation therapy

• Radiation therapy may be offered for blast phase CML for:

• Spleenomegaly
• Bone pain

Relapsed or Refractory Chronic Myelogenous

• Targeted therapy with a tyrosine kinase inhibitor may be offered for relapsed or refractory CML. For those already taking targeted therapy, the dose may be increased. The types of targeted therapy used are:

• Imatinib
• Dasatinib
• Nilotinib

Supportive Therapy

• Antibiotics and Antifungals
• Blood products

• Packed red blood cells
• Platelets
• Fresh frozen plasma
• Cryoprecipitate

• Growth factors

• Granulocyte colony-stimulating factors (G-CSF)

• Leukapheresis

References

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