Acute Lymphocytic Leukemia

Description

Alternative Names

Treatment After Relapse

Between 50% and 70% of children and 40% and 50% of adults who achieved complete remission after initial therapy and who relapse will achieve a second complete remission.

Treatment for relapse after a first remission may be standard chemotherapy, more aggressive treatments, such as bone marrow transplant, or investigative agents.

The decision depends on a number of factors:

• Children who relapse three or more years after achieving a first complete remission have an excellent chance for a second remission without aggressive treatments.
• Those who relapse less than six months following initial treatment, especially while on chemotherapy, have about a 20% chance of long-term freedom from disease. In such cases, remission is possible following another course of standard chemotherapy but the duration of remission is usually less than six months.

Treatment decisions also rely on prior treatments and where the relapse has occurred. Relapse can occur in the bone marrow, central nervous system, or sanctuary disease sites (brain, spine, or testicles). The incidence of relapse in sanctuary sites is about 10%.

Candidates for transplantation include the following:

• Patients who relapse following initial remission with standard chemotherapy.
• High-risk patients in first remission who are unlikely to be cured by standard chemotherapy alone. Many adult patients may fall into this category. Studies on high-risk children have been conflicting about the value of transplants during a first remission, with a 2000 study reporting no significant advantage. A 2001 study on children with the Philadelphia chromosome, however, suggested that this approach offered a better chance for a cure.
• Patients who fail to achieve a complete remission during initial chemotherapy.

Transplantation procedures do not appear to offer any additional advantages for patients at low or standard risk.

Transplantation Procedures

Transplantation procedures are based on stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments can harm these growing cells as well as cancer cells. In order to administer high-dose chemotherapy for advanced cancer cases, transplantation procedures typically first remove these stem cells either directly (hematopoietic blood stem cell transplantation) or from bone marrow (bone marrow transplantation). The patient is treated and the blood cells are restored.

Investigative Agents

Vaccines. Investigators are researching vaccines that use the body's own immune defenses to attack specific molecules, such as one called CD40, on the surface of leukemia cells.

Immunotoxins. Genetically engineered agents called immunotoxins fuses an antibody that targets specific factors in the tumor with a toxic molecule that destroys the cell. Some, such as BL22, is showing promise for patients with hairy cell leukemia and gemtuzumab ozogamicin (Mylotarg) is being studied for patients with acute myeloid leukemia. Experts are hoping such immunotoxins can also be useful for some patients with acute lymphocytic leukemia.

Nucleoside Analogs. These agents have widespread effects against leukemia and have been investigated for some time with mixed results. Some newer nucleoside analogs being studied for refractory or relapsed leukemia include troxacitabine (Troxatyl) and clofarabine (Clofarex). Fludarabine (Fludara), an older agent with severe toxicity at high doses, is typically investigated as part of regimens that also includes cytosine arabinoside (ara-C) (another nucleoside analog) and other chemotherapy agents.

Imatinib (Gleevac). Imatinib (Gleevac) is a new agent that blocks an enzyme called tyrosine kinase, which is an important component in the Philadelphia chromosome. It is proving to be very beneficial for patients with chronic myeloid leukemia (CML). Studies are also now reporting possible benefits for ALL patients who have the Philadelphia chromosome. In a 2002 study, many patients responded initially, but the response was followed by rapid progression. According to a 2003 study, imatinib combined with low-dose IFN-alpha results in prolonged remissions in patients who are not candidates for allogeneic stem cell transplant. Findings of a 2004 study helped to define the role of bone marrow status on the likelihood of response to imatinib. In the study, most patients with bone marrow blasts below 5% on day 14 were responders, whereas most patients with bone marrow blasts greater than 5% were nonresponders. More studies on combinations and reasons for resistance are needed.

Farnesyltransferase Inhibitors (FTIs). FTIs (e.g., Zarnestra) are agents that interfere with signals between cells to block an enzyme called farnesyltransferase, which is found in high levels in leukemia. Early trials are underway.

Monoclonal antibodies (MAbs). Used alone or in combination with chemotherapy, MAbs target specific antigens on ALL blast cells. Although MAbs have been studied primarily in the treatment of B-cell non-Hodgkins lymphoma, agents demonstrating benefit in preliminary trials of ALL include anti-CD20 (rituximab) and anti-CD22 (epratuzumab). More studies are needed to determine the best MAb regimens in ALL.

Transplantation Procedures for Acute Lymphatic Leukemia

In order to administer high-dose chemotherapy for advanced cancer cases, stem cell transplantation procedures may be used. Stem cell procedures have proven to produce long-term survival and even cures in patients with aggressive (intermediate and high-grade) non-Hodgkin's lymphomas. These procedures are based on removal and replacement of stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.

Collecting the Stem Cells

Sources of Cells. Stem cells must first be collected in one of the following ways:

• From bone marrow (bone marrow transplantation).
• Directly from blood (peripheral blood stem cell transplantation). Current evidence now appears to suggest that peripheral blood stem cell transplantation may be the superior approach. Studies are reporting survival rates of 45% in bone marrow transplant patients compared to 65% to 70% in stem cell transplant patients, with benefits being significant in those with more severe disease.
• From fetal umbilical cord or placentas. This procedure uses donor cells but has a lower risk for immune system rejection of the cells than with a standard donor transplant. It takes longer to restore blood cells with this process, however, so at this time its use is limited to children and sometimes adults with low weight. (Studies are now reporting some success for adults with normal weights.)

Donor or Patient Cells. The sources of marrow or blood cells can be taken from the patient or a donor:

• If the bone marrow or stem cells are taken from a donor, the transplant is referred to as allogeneic. Allogeneic transplants from genetically matched sibling donors offer the best results in ALL. With new techniques, donor bone marrow from unrelated but immunologically similar donors is proving to be as effective as those from matched siblings. This approach is still reserved for patients in second remission or beyond.
• If the marrow or blood cells are taken from an identical twin, the transplant is called syngeneic.
• If the marrow or blood cells used are the patient's own, the transplant is called autologous. Autologous transplants in ALL patients are generally not beneficial, since there is some danger that the cells used may contain tumor cells and the cancer can regrow. Treatment advances that reduce this risk, however, may make autologous transplantation feasible in patients without family donors.

The Blood Stem Cell Collection Procedure

• The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim) to stimulate stem cell growth.
• The donor (or patient in an autologous procedure) then undergoes apheresis. With this process the blood is withdrawn from one of the patients veins, then passes through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes three to four hours but needs to be repeated several times.
• The stem cells are then frozen.

The Transplant Procedure

• The patient is given high-dose chemotherapy with or without radiation a treatment known as conditioning. The point is to inactivate the immune system and to kill any residual malignant cells. Agents used are typically cyclophosphamide, carmustine, and etoposide. Alternative conditioning includes radiation with one agent.
• A few days after treatment, the patient is rescued using the stored stem cells, which are administered through a vein. This may take several hours. Patients may experience fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
• The patient is kept in a protected environment to minimize infection and he or she usually needs blood cell replacement and nutritional support.

Success Rates

Two- to five-year survival rates after transplantation plus chemotherapy range from 40% to 80%. Certain patients with the Philadelphia chromosome, which carries a poor prognosis, may achieve significant success with an allogeneic bone marrow transplant from a closely matched related donor.

Side Effects and Complications

Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite.

The procedures themselves are fairly dangerous and carry a small risk for death. When it was first used, transplantation procedures had 10% to 25% morality rates. Now mortality rates are below 5%. Potentially serious complications are the following:

• Infection resulting from a weakened immune system. This is the most common side effect and can persist for several months after the transplant. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. Many patients develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, cytomegalovirus, fungal infections, and Pneumocystis carinii (a protozoan) are among the most important life-threatening infections. Fungal infections are of particular concern because they are both very serious and their incidence is increasing with advances in conditioning treatments, immunosuppression and use of potent antibiotics. The patient may require very potent antibiotics and antifungal medications as well as granulocyte colony-stimulating factors or G-CSF (e.g. lenograstim, filgrastim) to stimulate the growth of infection-fighting white blood cells.
• Graft-versus-host-disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow. It occurs in over half of allogeneic transplants. GVHD can results in weight loss, bacterial infections, and skin and organ problems that may persist for up to three years after the procedure. In some cases it is fatal. Careful matching of the donor and preventive immunosuppressive drugs, such as corticosteroids, methotrexate, and cyclosporine (Sandimmune), may reduce the risk for this potentially life-threatening side effect. (There is some evidence that this reaction in allogeneic stem cell transplantation may have a positive side for certain Hodgkin's patients by actually attacking the lymphomas themselves. Studies to date, however, have not found that this offsets serious complications.)
• Secondary cancers. There is a small long-term risk for leukemia after transplantation in young people. Use of newer chemotherapeutic agents, however, may not pose as high a danger.
• Bleeding because of reduced platelets. This risk is highest within the first four weeks after BMT.
• Infertility.
• Organ complications to the liver, heart, kidney, or lungs.
• Failure of the transplant. The marrow graft may fail or new marrow cells may now grow.