Health Concerns

Leukemia

Conventional Treatment

The specific treatment approach depends upon the type of leukemia and how aggressive the disease is. Chemotherapy treatments compose the majority of leukemia therapy. Specialized drugs called tyrosine kinase inhibitors (TKIs) have become the mainstay of treatment for CML in most cases. These drugs work by interfering with the signaling of the BCR-ABL fusion gene, which is present in most CML patients and grants CML cells a survival advantage over normal cells (Bedi 1994; Guo 1996; Goldman 2012b; LLS 2012a). TKIs are also used in some ALL patients whose leukemia cells exhibit the Philadelphia chromosome (Fielding 2010; Wetzler 2012). Stem cell transplantation is also a viable option in some leukemia patients, especially those who fail to respond to first-line therapies or whose disease is considered high risk (Goldman 2012b; Goldman 2012a; Fielding 2010; Wetzler 2012).

First-line treatment is usually chosen based on the results of clinical trials in patients with the same type and stage of cancer. If the first-line treatment does not result in the desired outcome (ie, has serious side effects or does not induce an adequate response), oncologists usually recommend a second-line treatment (Baccarani 2009).

Patient-specific factors (eg, age) and disease-specific factors (eg, chromosomal characteristics of the type of leukemia) strongly impact prognosis and response to leukemia treatment. For many of the genetic mutations identified in the different leukemias, the impact on prognosis has not yet been determined (Liersch 2014). A notable example is the difference between ALL in children and adults. In children, ALL is a highly curable disease, with cure rates approaching 90% while in adults the cure rate is only 40% (Hunger 2012; ACS 2013d; UMMC 2013; Trigg 2008; Pui 2012).

Distinguishing “Cure” from “Complete Remission”

It is important that leukemia patients understand the meaning of various terms they may encounter during the course of their treatment. One area of potential confusion is the distinction between “cure” and “complete remission.”

When cancer has been completely eradicated from a patient’s body and is not expected to ever return, the patient is said to be “cured.” When all signs and symptoms of cancer have disappeared, but physicians cannot be sure that the cancer will never return, the patient is said to be in “complete remission.”

Physicians are often hesitant to say that a patient is “cured” of cancer because it is difficult to be certain that all the cancer has been eliminated from the patient’s body and that it will never return. Instead, physicians often say something along the lines of “there are no signs of cancer at this time.” However, some physicians may use the term “cured” to refer to patients who have been in complete remission for a long time, usually five years or more (NCI 2012).

Chemotherapy

Chemotherapy targets the growth of rapidly-dividing cells. Several drugs and drug combinations have been approved by the Food and Drug Administration (FDA) for the treatment of different types of leukemia. A complete list of drugs FDA-approved to treat leukemia is available at: http://www.cancer.gov/cancertopics/druginfo/leukemia.

Since chemotherapy destroys rapidly dividing cells, it also ends up destroying rapidly growing healthy cells, such as those of the gastrointestinal tract, skin hair follicles, nail matrix, mouth, reproductive system, and bone marrow (Mauch 1995; Tuncer 2012; Gradishar 1988; Kamil 2010; Herlofson 1997). This is why chemotherapy often causes unpleasant side effects, the most common of which are nausea and vomiting. Other side effects include changes in taste, fatigue, neuropathy, mouth sores, hair loss, and sexual dysfunction (CCS 2014). In addition, some leukemia cells develop drug resistance, resulting in treatment failure, which is one of the fundamental challenges facing patients, doctors, and the field of oncology (Wong 2012).

Acute leukemias. Patients diagnosed with acute leukemia usually need to start chemotherapy immediately after diagnosis. The first stage of chemotherapy is called the induction phase, in which the goal is induction of remission. During the induction phase, patients are administered intensive chemotherapy in attempt to eliminate leukemia cells from the blood and bone marrow. The exact combination of chemotherapy drugs used during the induction phase, as well as the duration and intensity of this phase, depend on several individual factors such as the patient’s age and health status, as well as the type and molecular characteristics of their leukemia. A port is placed, usually into a vein in the upper chest, to allow IV administration of the chemotherapy drugs. In AML, induction-phase treatment generally lasts about a week and usually takes place in a hospital setting. In ALL, treatment usually lasts a month or more and is intensive, requiring frequent doctor visits, with some patients spending part or all of the month in the hospital. If there is still evidence of leukemia cells in the patient’s blood and bone marrow after the first course of induction therapy, physicians may try a different combination of drugs (LLS 2014a; LLS 2011a; LLS 2012b; Goldman 2012a).

The second phase of chemotherapy, called post-remission therapy or consolidation therapy, consists of additional intensive chemotherapy and sometimes stem cell transplantation. The goal of post-remission therapy is to eliminate any remaining leukemia cells that linger, often in the bone marrow, after the induction phase. The duration of post-remission therapy depends on the characteristics of the leukemia, including cell type and other factors (LLS 2014a; LLS 2011a; LLS 2012b; Goldman 2012a).

Acute leukemia can infiltrate the brain and spinal cord; this is more common in ALL than AML (Schiffer 2003). In order to prevent this, chemotherapy is administered via injection into the spinal column; this is called central nervous system (CNS) prophylaxis. It is more common for ALL patients to receive CNS prophylaxis than patients with AML. Radiation therapy may also be employed during CNS prophylaxis (LLS 2014a; LLS 2011a; LLS 2012b; Goldman 2012a).

Chronic leukemias. For CLL, induction chemotherapy, antibody therapy, or a combination of the two is considered first-line treatment for patients with active, symptomatic disease or advanced disease. For CML, targeted drugs (particularly TKIs) represent first-line therapy, but chemotherapy is also used in some cases; stem cell transplantation is a therapeutic option for non-responsive cases and blast-phase patients (LLS 2012b; Paneesha 2014; Somervaille 2013). The goal of therapy is to produce a durable, lasting remission. Unfortunately, chronic leukemias are not considered curable by chemotherapy, but many patients achieve long-term remission (Paneesha 2014; Somervaille 2013; Goldman 2012b). The choice of chemotherapy drug(s) typically depends on the patient’s age and characteristics of their leukemia. For example, chlorambucil (Leukeran) is a standard drug used in CLL patients older than 65, while fludarabine (Fludara) is used in younger patients (Goldman 2012b; LLS 2012a; LLS 2011b).

Stem Cell Transplantation

Stem cells are primitive, undifferentiated cells that possess the ability to self-renew and differentiate into various cell types. Stem cell transplantation is the process of infusing healthy blood-forming stem cells to restore healthy bone marrow in leukemia patients that have undergone intensive treatment. When a patient’s own stored stem cells are transfused into their bloodstream, it is termed an autologous stem cell transplantation. Allogeneic stem cell transplantation, on the other hand, involves transplanting stem cells from a healthy donor whose tissue type closely matches the patient’s tissue type (ACS 2013c; Jaglowski 2012; Smolewski 2013).

When first introduced, allogeneic stem cell transplant, also known as bone marrow transplant, was called “the first important breakthrough in the evolution of CML treatment” as it was able to cure roughly 50% of the patients who underwent the procedure. These patients became Philadelphia chromosome-negative and BCR-ABL-negative. The greatest success of allogeneic stem cell transplant was in patients under the age of 40, but the median age at diagnosis for CML is close to 60 years (Baccarani 2014; ASCO 2013).

Tyrosine Kinase Inhibitors (TKIs)

The hallmark of CML is the Philadelphia chromosome, a breakage and fusion between regions on chromosomes 9 and 22. This gene fusion is referred to as BCR-ABL, and its product is a deregulated tyrosine kinase enzyme (Goldman 2008; Mauro 2001). Imatinib mesylate (Gleevec) is a TKI that targets leukemia cells harboring the BCR-ABL fusion gene; it showed unprecedented results in an early clinical trial involving 31 patients, inducing remission in all of them and eliminating evidence of the Philadelphia chromosome altogether in some. In a later study, the overall survival of patients who received imatinib as initial therapy was 89% at five years, and in another study, highly favorable responses were obtained in over 50% of patients who failed conventional therapies (Pray 2008; Druker 1996; Druker 2001; Druker 2006). Imatinib has two important limitations: it must be taken for life, or until it is no longer effective, and one of its side effects is serious water retention (edema) (Widmer 2006; ACS 2013e).

Specific mutations in the BCR-ABL gene make the enzyme resistant to imatinib therapy, as the drug is unable to target and stall the activity of BCR-ABL (Deininger 2005). Another troubling aspect of imatinib treatment is its cost-effectiveness. While imatinib has been shown to prolong life and improve quality of life in CML patients compared to conventional treatments, there is a significant cost associated with imatinib treatment (Gordois 2003; Warren 2004).

Other TKIs, referred to as second- and third-generation TKIs, have been developed and commercialized, namely dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif) and ponatinib (Iclusig). Clinical trials involving dasatinib and nilotinib have concluded that they are effective and generally well tolerated in CML patients who initially showed a suboptimal response to imatinib (Stein 2010; Baccarani 2014). Currently, dasatinib is approved as first-line treatment for all phases of CML as well as ALL patients with BCR-ABL gene fusion who respond suboptimally to imatinib (Hochhaus 2013). A third-generation TKI, ponatinib, has shown positive results in clinical trials on patients with the T315I mutation in BCR-ABL, which causes resistance to dasatinib and nilotinib (Breccia, Alimena 2014; Cortes 2013; Zhao 2013).

A major phase II clinical trial published in late 2013 examined the effects of ponatinib in patients with CML or Philadelphia chromosome-positive ALL. All subjects in this study had previously undergone intensive treatment and 1) were resistant to or had severe side effects from the second line TKIs dasatinib or nilotinib, or 2) had the BCR-ABL T315I mutation. Among 267 patients with chronic-phase CML, 56% had a “major cytogenetic response,” 46% had a “complete cytogenetic response,” and 34% had a “major molecular response.” Impressively, 91% of the “major genetic responses” were sustained for at least 12 months, and the researchers did not identify any single BCR-ABL mutation that caused resistance to ponatinib. Of 83 patients with accelerated-phase CML, 55% had a “major hematologic response” and 39% had a “major cytogenetic response.” Thirty-two of the trial participants had blast-phase CML, and 31% of them had a “major hematologic response” and 23% had a “major cytogenetic response.” Among 32 subjects who had Philadelphia chromosome-positive ALL, 41% had a “major hematologic response” and 47% had a “major cytogenetic response.” Common side effects included low platelet counts, rash, dry skin, and abdominal pain; serious treatment-related side effects were observed in 3% of subjects (Cortes 2013). Unfortunately, because of serious side effects involving blood clots, the indications for ponatinib use are limited to treatment of specific CML and ALL patient groups for whom no other TKI therapy is indicated (NCI 2014b).

Monoclonal Antibody-Based Therapy

Antibody-based therapy is a type of targeted therapy in which specific molecules called antibodies are administered to trigger the host’s immune system to target “markers” (called antigens) on cancer cells for elimination. Normally, antibodies are produced in the body by B cells. The antibodies identify disease-causing agents in the body, then trigger T cells and other components of the immune system to destroy them (Scott 2012; Lund 2010; Buss 2012; O'Mahony 2006; Vedi 2014).

Rituximab (Rituxan), a monoclonal antibody against the CD20 antigen on B cells, combined with chemotherapy is available for the treatment of B-cell ALL and CLL (Zhao 2013; Jaglowski 2010). Several studies suggest the addition of rituximab to intensive chemotherapy has improved the outcome for B-lineage ALL, particularly among younger adults. However, further investigation is needed to address the role of rituximab therapy in older patients (Thomas 2012; Hoelzer 2010). Another antibody being actively investigated is epratuzumab, which targets the CD22 antigen on B cells. One study investigated the addition of epratuzumab to the combination of Ara-C (Depocyt) and clofarabine (Clolar) in the treatment of one type of ALL in patients who relapsed or were resistant to previous therapy. The combination therapy resulted in a 52% response rate, whereas a previous trial of clofarabine/Ara-C alone only resulted in a 17% response rate (Advani 2012).

Another way antibodies are used in leukemia therapy is as a carrier for delivery of a cytotoxic drug directly to leukemia cells. This approach, called antibody-drug conjugation, is an active area of leukemia research (Cowan 2013; Ricart 2011; Vedi 2014; Wayne 2014). Combining therapeutic antibodies with specific toxins or radioactive agents holds the promise of greater efficacy compared to standard antibody-based therapy (Buss 2012). Gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin are composed of a toxin (a derivative of a toxic antibiotic with DNA-binding ability) linked to a human antibody against CD33 or CD22, respectively. CD33 and CD22 are specific markers of myeloid leukemia and B-cell malignancies, respectively (Cowan 2013; Ricart 2011).

Gemtuzumab Availability

After several clinical trials of gemtuzumab in patients with AML showed favorable results, the drug was given accelerated FDA approval in 2000. However, in 2010, it was withdrawn from the US and European markets due to lack of overall benefit in the entire study population in phase III studies and increased mortality observed in certain cases. The drug remained commercially available in Japan and received full regulatory approval (Ravandi 2012; Cowan 2013; ASH 2009). Recently, however, researchers have more rigorously analyzed data from large studies and concluded that gemtuzumab improved survival in well-defined subsets of leukemia patients with newly diagnosed non-APL AML. (Non-APL AML is characterized by the overproduction of primitive myeloid cells, or blasts.) Gemtuzumab may have similar efficacy in AML patients who have been genetically classified as low risk. Therefore, AML experts are asking the manufacturer and regulatory authorities to grant selected patients access to this potentially valuable medication (Ravandi 2012; Cowan 2013).

Interferon Therapy

Interferons are produced naturally in the body in response to viral infection, but they can also be synthesized and used as drugs (Pfeffer 1997; Perry 2005; Iqbal Ahmed 2003). Interferon-alpha (IFN-α) mediates anti-leukemic effects through diverse mechanisms involving stem cells and the immune system. For the past 50 years, various forms of interferon have been evaluated as therapy in a number of malignant and nonmalignant diseases (Jonasch 2001; Passegue 2009). Treatment of CML with IFN-α was introduced in the early 1980s and was found to be able to induce cytogenetic remission in 15-30% of patients, with a significant survival advantage compared to conventional chemotherapy (Baccarani 2014; Simonsson, Hjorth-Hansen 2011; Talpaz 1986). In several early studies, IFN-α, when combined with Ara-C, moderately improved clinical outcomes in CML patients (Ozer 1993; Robertson 1993; Kantarjian 1992; Simonsson, Hjorth-Hansen 2011).

A systematic review published in 2014 found that adding interferon to imatinib therapy in patients with CML was clinically more effective and led to earlier cytogenetic and molecular remission compared to imatinib alone. The combination was slightly more likely to cause hematologic side effects, but researchers concluded that it was safe in spite of this (Liu 2014).

Unfortunately, interferon therapy carries significant constitutional, neuropsychiatric, hematologic, and hepatic side effects, which can have a major impact on the patient’s quality of life (Jonasch 2001).

Recently, it was observed that a modified form of IFN-α, called PegIFNα2a (pegylated interferon alpha-2a), in combination with imatinib led to significant improvement in patients with low- or intermediate-risk CML and in chronic-phase CML. In this study, the combination required lower doses of IFN-α, which may enhance tolerability while retaining efficacy and could be considered in future combination therapies (Simonsson, Gedde-Dahl 2011; Johnson-Ansah 2013).

All-Trans Retinoic Acid

FDA-approved vitamin A-based therapies (retinoids) are available for the treatment of several malignancies (Bushue 2010; Tang 2011). In cancer, the therapeutic and preventive activities of retinoids are due to their ability to modulate the growth, differentiation, and survival of cancer cells (Altucci 2001). The influence of retinoids on cellular differentiation is of particular interest in the context of cancer (Gudas 2011). Cellular differentiation refers to the progression of a less-specialized cell to a more-specialized cell. Specialized cells originate from primitive precursor cells called stem cells. Stem cells are relatively undifferentiated in that they are not dedicated to function as a specific cell type – for example, as a white blood cell. As stem cells divide, they give rise to slightly more differentiated and specialized cells, which in turn divide and give rise to even more specialized cells. The process progresses until fully differentiated, specialized cell types are produced. In cancer, the process of cellular differentiation often becomes perturbed, giving rise to cells that may have the ability to divide and propagate, but do not function properly. Generally, the greater the degree of differentiation exhibited by cancer cells, the less aggressive they are and the more closely they resemble normal, healthy cells. Retinoids help regulate several genetic mechanisms that drive normal cellular differentiation, so they are used as cancer therapeutic agents in certain types of cancer (Gudas 2011; NCI 2014c; CIRM 2013; Nature Education 2014).

Vesanoid (Tretinoin) is a derivative of vitamin A. It is also referred to as all-trans retinoic acid (ATRA) (Bryan 2011). ATRA combined with arsenic trioxide is, as of the time of this writing, largely considered the treatment of choice for the AML subtype known as acute promyelocytic leukemia (APL) (Siddikuzzaman 2011; Watts 2014).

An early study that measured five-year disease-free survival in APL patients showed that chemotherapy supplemented with ATRA was more effective than daunorubicin (Cerubidine) and cytarabine (Depocyt) (Tallman 2002). In a study of newly diagnosed APL patients, the combination of ATRA and arsenic trioxide resulted in significant shortening of the time required to attain complete remission (Shen 2004). Later clinical studies showed that the combination of ATRA with regular chemotherapy treatment caused minimal toxicity and was highly effective in treating newly diagnosed APL patients (Hu 2009; Sanz 2008). In APL patients considered low-to-medium risk, the combination of ATRA and arsenic trioxide has made traditional chemotherapy unnecessary in many cases. In patients treated with ATRA and arsenic trioxide in the induction and consolidation phases of treatment, overall survival rates greater than 90% have been observed (Siddikuzzaman 2011; Watts 2014; Breccia, Cicconi 2014; Wang 2011; Chen 2014; Lo-Coco 2013).

In one study, the addition of ATRA to chemotherapy demonstrated increased rates of remission and survival in elderly patients with AML (Schlenk 2004). In laboratory studies examining resistance to the TKI medications imatinib, nilotinib, or dasatinib, ATRA blocked acquisition of BCR-ABL mutations and resistance to these medications (Wang 2014).

Surgery

Because leukemia is not isolated in a tumor but disseminated throughout the body in the blood, surgery is not a useful treatment for the majority of cases. However, surgery may be helpful in treating certain leukemia complications. For example, in some leukemia patients the spleen becomes enlarged and can compress nearby organs, causing discomfort or other complications. In these cases, when radiation or chemotherapy do not shrink the spleen, it can be surgically removed (splenectomy) (ACS 2014b).

Tumor Lysis Syndrome

Tumor lysis syndrome is a potentially life-threatening complication of cancer treatment. It occurs as a result of rapid decomposition of cancer cells after therapy, which can lead to metabolic imbalances and give rise to acute kidney injury, seizures, and cardiac arrhythmias. Most cases of tumor lysis syndrome occur in patients with blood-related cancers (Mughal 2010; Flombaum 2000).

Leukemia patients have an increased risk for developing tumor lysis syndrome. Therefore, it is important that they are carefully monitored by a physician for signs of tumor lysis syndrome (Ezzone 1999; Doane 2002; Gobel 2002).

Diligent preventive measures may help prevent tumor lysis syndrome. For a few days before therapy is initiated, the patient should be adequately hydrated, and a drug called acetazolamide (Diamox) may be administered to help alkalinize the urine. Allopurinol (Zyloprim), a drug to help prevent the buildup of uric acid in blood, is often used as well (Goldman 2012a).