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Patient information: Acute lymphoblastic leukemia (ALL) treatment in adults (Beyond the Basics)

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Richard A Larson, MD
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Bob Lowenberg, MD, PhD
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Rebecca F Connor, MD
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ACUTE LYMPHOBLASTIC LEUKEMIA OVERVIEW

Acute lymphoblastic leukemia (also called ALL) is a cancer of the blood cells. It affects a type of white blood cell called a lymphocyte. ALL is also known as lymphoblastic lymphoma when the disease primarily involves lymph nodes rather than the blood and bone marrow. "Acute" means that it develops and advances quickly, and requires immediate treatment.

Normally, lymphocytes and other blood cells are produced by the bone marrow (the spongy area in the middle of bones) in a controlled fashion. In someone with ALL, this process is abnormal. Large numbers of immature and abnormal lymphocytes (called lymphoblasts) are produced and released into the bloodstream. In their immature state, these cells cannot perform their usual functions. The overgrowth of these cells leads to an inadequate number of normal, healthy blood cells, including white blood cells, red blood cells, and platelets. This can result in:

Neutropenia (low numbers of neutrophils) – Neutrophils are a type of white blood cells that help to fight infection. People with neutropenia are more likely to get infections.

Anemia (low numbers of red blood cells) – Red blood cells carry oxygen to our tissues. People without enough red cells may be pale and are often tired and short of breath.

Thrombocytopenia (low numbers of platelets) – Platelets help to prevent and stop bleeding. People with low platelets have bleeding and spontaneous bruising.

There are several types of ALL. The three main subtypes are B cell ALL, T cell ALL, and Philadelphia chromosome positive ALL (also called Ph+ ALL). B cell ALL is the most common type. Ph+ ALL is a subtype of B cell ALL that accounts for about one-third of all adult ALL, but is uncommon in children. While the general principles are the same, the specifics of treatment differ according to subtype. As an example, treatment of patients with Ph+ ALL includes specific drugs that target the gene product of the Philadelphia chromosome.  

More detailed information about ALL, written for healthcare providers, is available by subscription. (See 'Professional level information' below.)

GENERAL INFORMATION ABOUT ALL TREATMENT

A number of medications, or chemotherapy agents, are known to be effective against ALL. However, the best combination of medicines or the best treatment schedule is still not known. Because there are so many different medicines, dosing schedules, and combinations, it has been difficult to study any one component of treatment thoroughly.

However, general principles of treatment have emerged and are followed in most cancer treatment centers. The exact regimens may vary from one center to another. Regimens can also vary based upon individual characteristics such as your ALL subtype, whether there are ALL cells in the fluid that surrounds your brain and spinal cord, your age, and your general health.

Treatment side effects — Side effects of treatment will depend on the actual medicines being used, the schedule of treatment, and other factors. Many of the chemotherapy medicines used to treat ALL share common side effects such as temporary hair loss, nausea and vomiting, mouth sores, diarrhea or constipation, numbness of fingertips and toes, and an increased risk of infections and bleeding. Treatment to minimize these side effects is available.

Phases of treatment — The usual treatment for ALL can be divided into three phases: induction of remission, post-remission consolidation/intensification of therapy, and remission maintenance (also called continuation therapy). Each of these phases is important for destroying the cancer cells and preventing recurrence.

Induction of remission – In this phase, several medications are given with the goal of destroying as many cancer cells as possible to achieve a remission, meaning there are no detectable lymphoblasts in the blood or bone marrow and the normal blood cells have returned. This phase of treatment usually lasts four to six weeks and most of the time is spent in the hospital. Sometimes several courses of induction therapy are needed to achieve remission.

Consolidation/intensification therapy – This phase happens after remission has been achieved, and involves more chemotherapy, other medications, and/or stem cell transplantation to prevent a relapse. Chemotherapy is usually given in cycles for four to six months.

Remission maintenance (or continuation) therapy – This involves alternating chemotherapy sessions with oral medications (pills), usually over two to three years. Most people are able to return to their normal activities during their maintenance treatment period.

INDUCTION OF REMISSION

Induction of remission takes about four weeks and is almost always performed while the patient remains in the hospital. Treatment usually includes vincristine and a steroid hormone (such as prednisone or dexamethasone) and may include an anthracycline (such as daunorubicin or doxorubicin). An enzyme called asparaginase is often given intravenously to starve malignant lymphoblasts of the essential amino acid asparagine in the plasma. Patients with Philadelphia chromosome positive ALL require the addition of a BCR-ABL tyrosine kinase inhibitor (called a TKI), such as imatinib or dasatinib. Sometimes the TKI is used in combination with more conventional chemotherapy and sometimes it is given with dexamethasone only during induction, and then continued for several years. Patients with CD20-positive ALL (in which a protein called CD20 is found on the surface of certain cells) may also be treated with a monoclonal antibody directed against CD20, called rituximab.

Vincristine and the anthracycline drugs are anti-cancer chemotherapy drugs. Chemotherapy refers to the use of medicines to stop or slow the growth and longevity of cancer cells. Chemotherapy targets growing cells, interfering with their ability to divide or multiply. Because most of an adult's normal cells are not actively growing, they are not as affected by chemotherapy as the cancer cells. However, the cells in the bone marrow (where the blood cells are produced), the hair follicles, and the lining of the gastrointestinal (GI) tract are all growing. Effects of chemotherapy on these and other normal tissues cause side effects during treatment, including hair loss, nausea, anemia (lowered red blood cell count), an increased risk of infection (lowered white blood cell count), and bleeding (lowered platelet count).

Vincristine and the anthracycline drugs are given through an intravenous (IV) line. Prednisone or dexamethasone can be given either by mouth or IV. Other medicines such as cyclophosphamide (Cytoxan, given IV) or pegylated asparaginase (given as a subcutaneous, intramuscular or IV injection) may also be given.

Approximately 80 percent of newly diagnosed adults with ALL enter complete remission after the initial treatment. This means that there are no detectable lymphoblasts in the blood or bone marrow and that the bone marrow is functioning normally. However, such remissions are usually short-lived unless additional chemotherapy is given (see 'Consolidation/intensification therapy' below).

Very sensitive pathology tests (flow cytometry and molecular methods) may be able to detect tumor cells that cannot be identified using routine examination of the blood or bone marrow. Tumor cells detected by these tests are called "minimal residual disease" (also called MRD). Detection of MRD at the end of induction might change the treatment plan since even small numbers of ALL cells can lead to relapse.

CONSOLIDATION/INTENSIFICATION THERAPY

Once remission is achieved, additional therapy is needed to avoid relapse. Relapse probably occurs because abnormal cells are still present, even though these cells cannot be detected by routine examination of the blood or bone marrow. The intensity of consolidation therapy will depend upon the anticipated risk of relapse and the risks associated with treatment. Chemotherapy without stem cell transplant is usually preferred for ALL in first remission with a standard risk of relapse. Stem cell transplant is usually reserved for ALL in first remission with a higher risk of relapse and for those who have already relapsed and achieved a second remission (see 'Stem cell transplantation' below). This is because there is no clear survival advantage to stem cell transplantation over consolidation chemotherapy for standard risk patients in their first complete remission, although it may shorten the overall treatment course.

Consolidation chemotherapy — Some of the same medicines given during induction are also used during post-remission consolidation therapy, which may last for several months. Most of this treatment can take place as an outpatient during the day, without the need to remain in the hospital overnight.

In addition to scheduled doses of chemotherapy, many treatment programs call for preventive treatment of the central nervous system (the brain and spinal cord). Abnormal lymphoblasts in the brain often do not respond to chemotherapy given only into a vein, but must be treated directly with radiation to the head and/or, more often, injection of chemotherapy, such as methotrexate, into the cerebrospinal fluid (CSF) surrounding the spinal cord and brain through a lumbar puncture (also called a spinal tap).

Stem cell transplantation — Stem cell transplantation, also called bone marrow transplantation or hematopoietic stem cell transplantation, is a treatment in which the patient’s normal source of blood cells (the bone marrow) is replaced by healthy young blood cells (called stem cells) from a healthy well-matched donor. (See "Patient information: Stem cell transplantation (bone marrow transplantation) (Beyond the Basics)".)

Patients with ALL may undergo allogeneic transplantation, which uses stem cells from a donor other than the patient, ideally a sibling with a similar genetic makeup (called a matched related donor). If the patient does not have a sibling with similar genetic characteristics, an unrelated person with a similar genetic makeup may be used (called a matched unrelated donor). Another possibility is to use a sibling with partially similar genetic characteristics, although this is not as well studied (sometimes called a partially matched family member donor). Umbilical cord blood can also provide a source of unrelated stem cells.

In preparation for transplant, patients with ALL are usually given very high doses of chemotherapy or total body irradiation (TBI), called myeloablative conditioning. This kills cancer cells but also destroys all normal cells developing in the bone marrow. This means that the body's normal source of blood cells (the bone marrow) is no longer functional. The transplanted cells re-establish the blood cell production process in the bone marrow.

Reduced-intensity conditioning and nonmyeloablative conditioning are less intensive treatments that can prepare the bone marrow for transplantation and are being studied in older patients and others who are not candidates for myeloablative treatment.

A large part of the curative effect against ALL comes from the cytotoxic (toxic to living cells) effects of chemotherapy or radiation therapy, but there is also part that comes from the transplantation of a new immune system into the patient. These new immune cells, which are derived from the donor, can have an independent anti-leukemic effect that can eradicate residual ALL cells that otherwise survive the conditioning regimen.

Allogeneic transplantation uses stem cells from a donor other than the patient, ideally a sibling with a similar genetic makeup (called a matched related donor, or MRD). If the patient does not have a sibling with similar genetic characteristics, an unrelated person with a similar genetic makeup may be used (called a matched unrelated donor). Another possibility is to use a sibling with partially similar genetic characteristics, although this is not as well studied (sometimes called a partially matched family member donor). Umbilical cord blood can also provide a source of unrelated stem cells.

Allogeneic transplantation treats ALL in two ways. First, high doses of chemotherapy or total body irradiation are given immediately before the transplant, which aggressively attacks and kills the leukemia cells present in the blood and bone marrow. Second, when cells from another person are transfused, some of the donor stem cells mature into immune cells, and these donor immune cells can cause an immune response that helps destroy any remaining leukemia cells. This is called the "graft-versus-leukemia" or "graft-versus-tumor" effect. Unfortunately, this response is closely associated with a complication called "graft-versus-host disease" in which the immune response includes an attack on some of the patient's own healthy organs. Symptoms can include severe skin rash, diarrhea, liver damage, and other problems.

Autologous transplantation, which uses the patient's own stem cells collected while the patient is in complete remission, is of no greater benefit than chemotherapy for adults with most subtypes of ALL. Thus, it is generally not recommended. However, preliminary results with autologous transplantation for patients with Philadelphia chromosome positive (Ph+) ALL who achieve a complete molecular remission have been encouraging.

MAINTENANCE THERAPY

Remission maintenance therapy or remission continuation therapy is a standard part of ALL treatment, although research studies have not clearly shown its benefit for adults. It is also unclear how long therapy should continue. Depending upon the program chosen, treatment is often continued for two to three years.

During maintenance treatment, oral medications (pills) are taken on certain days of the month and intravenous (IV) chemotherapy may be given into a vein once per month. Side effects during this phase of treatment are less frequent and less severe than those experienced during earlier stages of treatment. Most people are able to return to their normal activities during their maintenance treatment period.

RESIDUAL DISEASE AND RELAPSE RISK

Following the standard two to three years of treatment, patients in complete clinical remission should be monitored closely for evidence of early relapse. This involves regular bone marrow aspiration and biopsy to check blood counts and look for lymphoblasts. This allows for early detection and treatment if relapse were to occur. Patients with ALL who maintain complete, continuous remission for four to five years are considered cured and no longer need routine bone marrow examination. However, relapses of ALL as long as 21 years after diagnosis have been reported.

Unfortunately, up to 25 percent of adults with ALL have disease that is resistant to the initial induction of remission. In addition, many adults with ALL who do attain an initial complete remission will ultimately suffer a relapse. Although a second remission can often be achieved, re-treatment of such patients is generally unsuccessful in the long run, and most will die of their disease or of complications of treatment. Allogeneic stem cell transplantation is generally recommended for patients who attain a second remission.

Treatment of relapsed or resistant disease — A second remission may be attained using a similar induction regimen if the relapse occurs more than two years following initial treatment. However, this approach is not recommended if a patient has primary resistant disease (complete remission was never attained) or for those who relapse while receiving induction or maintenance therapy.

Several novel anti-leukemia medications have been approved for specific subtypes of ALL. Immune-based (non-chemotherapy) treatments have been developed and are becoming more widely available. Salvage regimens, also called rescue treatments, are used after standard frontline treatments have failed. These regimens are designed to reduce symptoms and prolong survival, but may not be able to cure the disease. Optimally, patients should enroll onto a clinical trial specifically designed for treatment of resistant or relapsed ALL so they can get access to new agents given either alone or in combination.

Allogeneic stem cell transplantation is a reasonable option for selected patients with resistant or relapsed disease. All eligible patients who achieve a second complete remission should consider allogeneic stem cell transplantation.

CLINICAL TRIALS

Many patients with leukemia will be asked to enroll on a clinical research trial. Clinical research trials have advanced our knowledge and been crucial in the development of modern ALL therapy. Agents that are useful for relapsed disease are now being tested for patients with newly diagnosed ALL.

A clinical trial is a controlled way to study the effectiveness of new treatments or new combinations of known therapies. They are carefully designed and reviewed by experts in the field to provide state-of-the-art care for individual patients as well as to improve the outcomes of patients overall. Additional information concerning clinical trials for ALL can be obtained from the treatment team or the following websites:

www.cancer.gov/clinicaltrials

http://clinicaltrials.gov

Videos addressing common questions about clinical trials are available from the American Society of Clinical Oncology (http://www.cancer.net/pre-act).

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient information: Acute lymphoblastic leukemia (ALL) (The Basics)
Patient information: Leukemia in adults (The Basics)
Patient information: Neutropenia and fever in people being treated for cancer (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient information: Stem cell transplantation (bone marrow transplantation) (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Clinical manifestations, pathologic features, and diagnosis of precursor B cell acute lymphoblastic leukemia/lymphoma
Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma
Cytogenetics and molecular genetics in acute lymphoblastic leukemia
General principles of hematopoietic cell transplantation for acute lymphoblastic leukemia in adults
Treatment of relapsed or refractory acute lymphoblastic leukemia in adults
Induction therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults
Post-remission therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults
Induction therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults
Post-remission therapy for Philadelphia chromosome positive acute lymphoblastic leukemia in adults

The following organizations also provide reliable health information.

National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)

National Cancer Institute

(www.cancer.gov/cancertopics)

American Cancer Society

(www.cancer.org)

The Leukemia & Lymphoma Society

(www.leukemia-lymphoma.org/hm_lls)

The American Society of Hematology

(www.hematology.org)

National Marrow Donor Program

(www.marrow.org)

The American Society of Clinical Oncology

(www.cancer.net/all)

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Literature review current through: May 2016. | This topic last updated: May 4, 2016.
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