Treatment After Relapse

Between 50 - 70% of children and 40 - 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 or investigative drugs, or more aggressive treatments such as stem cell transplants.

The decision depends on a number of factors:

• Children who relapse 3 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 6 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 6 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.

Chemotherapy Drugs Used After Relapse

Many different drugs are used to treat ALL relapses. These drugs include vincristine, L-asparaginase, anthracyclines (doxorubicin, daunorubicin), cyclophosphamide, cytarabine (ara-C), and epipodophyllotoxins (etoposide, teniposide). Corticosteroids, such as prednisone or dexamethasone, may also be used. Although it is not yet approved for ALL, many doctors use imatinib (Gleevec) to treat patients with the Philadelphia chromosome. In 2004, the FDA approved clofarabine (Clolar) for treatment of relapsed or refractory ALL in children. This drug was the first new leukemia treatment approved specifically for young patients in more than a decade. In 2005, nelarabine (Arranon) was approved to treat adults and children with relapsed or refractory T-cell acute lymphocytic leukemia (T-ALL).

Investigative Drugs

Tyrosine kinase inhibitors. Tyrosine kinase is a growth-stimulating protein. Tyrosine kinase inhibitor drugs block the cell signals that trigger cancer growth. Several tyrosine kinase inhibitors are showing a great deal of promise in treating different types of ALL:

• Imatinib (Gleevec) has shown benefits in many studies as a first-line treatment for patients with Philadelphia chromosome positive ALL. The drug is currently approved to treat chronic myeloid leukemia (CLL). It is in Phase II trials for ALL.
• AMN-107 has produced excellent results in patients with Philadelphia chromosome positive ALL who are resistant to imatinib. Some experts predict that this drug will eventually become the standard of care for patients with this type of cancer. It is in Phase I/II trials.
• BMS-354825 has shown promise in Phase I trials as another treatment for patients with Philadelphia chromosome positive ALL. Like AMN-107, this drug blocks a type of tyrosine kinase called Bcr-Abl.

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-Hodgkin's lymphoma, drugs demonstrating benefit in preliminary trials of ALL include anti-CD20 (rituximab) and anti-CD22 (epratuzumab). Alemtuzumab (MabCampath) is also showing promise in treating relapsed or refractory T-ALL. More studies are needed to determine the best MAb regimens in ALL.

Transplantation Procedures for Acute Lymphocytic Leukemia

In order to administer high-dose chemotherapy for advanced cancer cases, stem cell transplantation procedures may be used. 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 either 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 - 70% in stem cell transplant patients, with benefits being significant in those with more severe disease.
• 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 patients with ALL 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 patient's 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 3 to 4 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. Drugs used are typically cyclophosphamide, carmustine, and etoposide. Alternative conditioning includes radiation with drugs.
• 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 5-year survival rates after transplantation plus chemotherapy range from 40 - 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 - 25% morality rates. Now mortality rates are below 5 percent. Potentially serious complications include:

• 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, and fungal infections 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 strong 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, may reduce the risk for this potentially life-threatening side effect.
• Secondary cancers. There is a small long-term risk for leukemia after transplantation in young people. Use of newer chemotherapeutic drugs, however, may not pose as high a danger.
• Bleeding because of reduced platelets. This risk is highest within the first 4 weeks after bone marrow transplantation.
• Other side effects include heart, lung, and liver complications, infertility, transplant failure, muscle problems (stiffness, cramps, joint pain), frequent urination, and bladder control problems.
• Older patients should be screened for osteoporosis and hypothyroidism (underactive thyroid).

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Review Date: 12/17/2005
Reviewed By: Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital