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%).

Nilotinib

Nilotinib (Tasigna, Novartis Pharmaceutical Corporation, NJ) is a structural analog of imatinib, though its affinity for the ATP binding site on BCR-ABL is up to 50 times more potent in vitro [23]. Like dasatinib, nilotinib initially demonstrated the ability to induce hematologic and cytogenetic responses in patients who had failed imatinib. Similar to the data with dasatinib, nilotinib has also been directly compared with imatinib in a large, international, randomized study. In ENESTnd, two doses of nilotinib (300 or 400 mg twice daily) were compared with imatinib 400 mg once daily [24]. The primary endpoint in this study was the rate of major molecular response (MMR) at 12 months. This endpoint was achieved at statistically significantly higher rates for both doses of nilotinib compared with the imatinib group (44 and 43% vs. 22%, P < 0.001). There was also much less progression to AP or BP on the nilotinib arm. Recently, a 36 month follow-up was published, and differences in deep molecular responses continued to favor nilotinib at either dose [25]. Current guidelines recommend any of the three TKIs: imatinib, dastinib, or nilotinib as options with a category 1 recommendation for initial treatment of CML-CP [26]. Second generation TKIs have shown inducing higher rates of early optimal responses; their impact on long-term over survival remains to be determined. AlloHSCT or other chemotherapy agents are not any longer recommended as upfront treatments for CML-CP given the excellent outcomes and long-term survival achieved with the TKIs. PMID:24729196

Initial treatment of chronic phase CML

Tyrosine kinase inhibitors (TKIs) have transformed outcomes in CML. The pivotal IRIS study demonstrated far superior rates of CHR, CCyR and MMR in imatinib- compared to interferon-treated patients and a superior PFS.^{33, 34} Prior to the IRIS study, other than interferon-based therapy, allogeneic stem cell transplant (alloSCT) was the treatment of choice for eligible patients and achieved long-term disease-free survival (DFS) in approximately 50–85% of patients^35–39 due to a graft-vs-leukemia (GVL) effect.⁴⁰ AlloSCT is associated with a unique toxicity profile, particularly opportunistic infections and graft-vs-host disease (GVHD), resulting in treatment-related mortality of 5–20% and significant morbidity in many long-term survivors. Combined with the dramatic success of TKIs, alloSCT is now reserved for patients with advanced stage disease or treatment failure; this is discussed in more detail in later sections. Three TKIs are now FDA-approved for initial treatment of CP-CML: imatinib, nilotinib and dasatinib.

Treatment of accelerated phase CML

Criteria for the diagnosis of AP-CML have been outlined earlier. ABL1 mutations increase in frequency in advanced-stage disease; mutational evaluation should therefore be performed and TKI choice based on this.^{68, 73} The optimal therapeutic approach in AP-CML differs according to whether the patient is TKI-naïve or has progressed from chronic phase while taking a TKI. Eighty to ninety percent of treatment-naïve patients will achieve CCyR with TKI^{93, 94} and have a similar EFS and OS to patients presenting in chronic phase, particularly when treated with 2^nd generation TKI. Those patients with cytogenetic clonal evolution as the only criterion for AP also have superior outcomes to those with hematologic/clinical features of AP.⁹⁵ In contrast, much lower response rates and inferior EFS, with continued relapses, have been seen in studies of 2^nd generation TKIs in patients with imatinib failure and AP disease.^{96, 97}

Treatment options include a TKI or alloSCT (either de novo or after initial TKI therapy). There is no randomized data to guide the choice or dose of TKI. However, there is a suggestion from non-randomized studies that 2^nd generation TKIs have superior response rates to imatinib⁹³, and ponatinib provides perhaps the best outcome.

There is also no randomized data to guide the decision to perform alloSCT for patients with AP-CML. In the pre-imatinib era, patients transplanted in AP had 30–40% disease-free survival at 4y compared to 70–80% for CP.^{98, 99} Non-randomized data suggests superior outcomes in patients treated with imatinib followed by alloSCT compared to imatinib alone, but there is the standard selection bias in this study.¹⁰⁰

In summary, patients with de novo AP-CML may have good outcomes, particularly if treated with a 2^nd-generation TKI. We treat these patients following the same guidelines we use for CP patients, and alloSCT is only considered upon failure of 2 TKI. However, patients with AP developing after imatinib failure have significantly poorer outcomes and may be best treated more aggressively with a 2^nd generation TKI followed by alloSCT when eligible. Patients with excellent, rapid responses to the second TKI may be followed closely and alloSCT considered only if showing recurrence. Another important question for which there is no data to guide decisions is the role of maintenance TKI post-transplant. Our practice is to continue TKI post-transplant after count recovery for patients who previously progressed to AP or BP.

Treatment of blast phase CML

Criteria for BP progression were outlined above. Approximately 50–60% of patients have myeloid blast phase (MBP) and 20–30% lymphoid blast phase (LBP). The remaining 10–30% are mixed:¹¹ The aim of treatment is to achieve reversion to chronic phase, then perform alloSCT +/− post-transplant TKI maintenance.

Treatment of LBP

Induction chemotherapy is given as per de novo acute lymphoblastic leukemia (ALL), with the addition of a TKI. Chemotherapy with hyper-fractionated vcyclophosphamide, vincristine, adriamycin and dexamethasone (hyper-CVAD) + TKI can achieve CHR in approximately 90% of patients.¹⁰¹ Most patients will have previously received a TKI. However, in patients presenting with de novo transformation, it is important (although sometimes difficult) to distinguish CML in LBP from Philadelphia chromosome (Ph)-positive ALL: morphologic criteria to suggest pre-existing CML, such as monolobated megakaryocytes and basophilia, may be useful, as is the the BCR-ABL transcript type; p210 BCR-ABL is present in most CML-LBP, while most Ph-positive ALL has the p190 transcript). Mutations in BCR-ABL1 in patients who have failed imatinib are more frequent in BP (73%) relative to CP/AP;¹⁰² the use of ABL1 mutational analysis to guide treatment is therefore essential. T315I is very frequent and, in contrast to CP, may be identified even before exposure to a TKI; these patients require treatment with ponatinib, usually combined with chemotherapy (hyper-CVAD, in our hands). Additional chromosomal abnormalities are frequent (particularly monosomy 7)¹⁰¹ and outcomes are generally poor. AlloSCT after initial response appears to improve outcomes, but selection bias in such studies is inevitable.¹⁰¹

Treatment of MBP

CML-MBP has a poor response to standard acute myeloid leukemia (AML) induction regimens.¹⁰³ De novo MBP patients may respond to TKI monotherapy, but responses are shallow and transient.^{104, 105} There are few studies of AML induction chemotherapy or low-dose cytarabine combined with TKI.^{106, 107} Our general approach is to give standard AML induction chemotherapy with the addition of a TKI and perform alloSCT in responding patients.¹⁰⁸ Although outcome for patients with prior BP is better when there is only minimal residual disease or no detectable disease even by PCR, we recommend alloSCT as soon as a patients is back to CP or has CHR as continued chemotherapy is no guarantee of improved response and may cause complications that can disqualify the patient for a later transplant.

Which TKI should be used in blast phase CML

There is no head-to-head data in this area and much existing data concerns use of single agent TKIs, which are rarely used in practice. Imatinib 600mg results in shallow and transient single-agent responses.^{104, 105} Imatinib does not cross the blood-brain-barrier, so is inadequate when central nervous system involvement exists.^{109, 110} Dasatinib 140mg per day achieves a significantly higher rate of CCyR (26 and 46% in MBP and LBP, respectively), but responses are again transient, with a median survival of <12mo for MBP and <6mo for LBP.¹¹¹ Although dasatinib crosses the blood-brain barrier, we do not rely on this for prophylaxis or management of CNS disease and give standard treatment with intrathecal chemotherapy, high-dose systemic chemotherapy and occasionally radiotherapy to approach this issue. Nilotinib 400mg BID is associated with no better results compared to dasatinib and is not approved for this indication.⁷⁶ Bosutinib is also approved for blast phase and may induce hematologic response in 28% and MCyR in 37%.¹¹² Ponatinib has resulted in favorable response in heavily pre-treated patients and patients with T315I mutations. Approximately 50% patients had a hematologic response after failure of dasatinib or nilotinib in MBC or LBC¹¹³ and 18% achieved CCyR. 1 year survival was an impressive 55%. Whenever possible, we use ponatinib as this might be the most effective agent and covers all mutations. Dasatinib and bostunib are suitable alternatives. PMID:26434969

treatment

The goal of chronic myelogenous leukemia treatment is to eliminate the blood cells that contain the abnormal BCR-ABL gene that causes the overabundance of diseased blood cells. For most people, it's not possible to eliminate all diseased cells, but treatment can help achieve a long-term remission of the disease.

Targeted drugs

Targeted drugs are designed to attack cancer by focusing on a specific aspect of cancer cells that allows them to grow and multiply. In chronic myelogenous leukemia, the target of these drugs is the protein produced by the BCR-ABL gene — tyrosine kinase. Targeted drugs that block the action of tyrosine kinase include:

• Imatinib (Gleevec)
• Dasatinib (Sprycel)
• Nilotinib (Tasigna)
• Bosutinib (Bosulif)
• Ponatinib (Iclusig)

Targeted drugs are the initial treatment for most people diagnosed with chronic myelogenous leukemia. If the disease doesn't respond or becomes resistant to the first targeted drug, doctors may consider other targeted drugs, such as omacetaxine (Synribo), or other treatments. Side effects of these targeted drugs include swelling or puffiness of the skin, nausea, muscle cramps, rash, fatigue, diarrhea, and skin rashes.

Doctors haven't determined a safe point at which people with chronic myelogenous leukemia can stop taking targeted drugs. For this reason, most people continue to take targeted drugs even when blood tests reveal a remission of chronic myelogenous leukemia.

Blood stem cell transplant

A blood stem cell transplant, also called a bone marrow transplant, offers the only chance for a definitive cure for chronic myelogenous leukemia. However, it's usually reserved for people who haven't been helped by other treatments because blood stem cell transplants have risks and carry a high rate of serious complications.

During a blood stem cell transplant, high doses of chemotherapy drugs are used to kill the blood-forming cells in your bone marrow. Then blood stem cells from a donor or your own cells that were previously collected and stored are infused into your bloodstream. The new cells form new, healthy blood cells to replace the diseased cells.

Chemotherapy

Chemotherapy drugs are typically combined with other treatments for chronic myelogenous leukemia. Often, chemotherapy treatment for chronic myelogenous leukemia is given as a tablet you take by mouth. Side effects of chemotherapy drugs depend on what drugs you take.

Biological therapy

Biological therapies harness your body's immune system to help fight cancer. The biological drug interferon is a synthetic version of an immune system cell. Interferon may help reduce the growth of leukemia cells. Interferon may be an option if other treatments don't work or if you can't take other drugs, such as during pregnancy. Side effects of interferon include fatigue, fever, flu-like symptoms and weight loss.

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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