Post-Remission Treatment

Overview

If a complete remission is achieved following remission-induction therapy and no further treatment given, over 90% of patients will have a recurrence of leukemia in weeks to months. However, treatment of standard-risk children with ALL with intensive post-remission therapy can cure 70-80%. It is important to understand what determines the success or failure of treatment in order to ensure the appropriate treatment for an individual patient. Post-remission therapy in standard-risk children with ALL typically consists of treatment with more than one cycle of multi-agent intensive chemotherapy combined with preventive treatment (prophylaxis) of the central nervous system and prolonged low-dose "maintenance" chemotherapy for 1-3 years. Children at high risk of relapse are treated with more intensive chemotherapy often associated with autologous or allogeneic stem cell transplantation.

Risk Factors

The major determinants of outcome among children with ALL are the presence of adverse risk factors and the intensity of post-remission therapy. These risk factors include:

  • Age: Age at diagnosis is very important. Children who develop ALL in the first year of life have a very poor prognosis, especially if their leukemia cells contain a mutated gene called MLL. Children over the age of 9 years also have a relatively poor prognosis.
  • White Blood Cell Count (WBC): A WBC at diagnosis of 50,000 per microliter is associated with a poor prognosis and is often associated with other poor risk factors.
  • Central Nervous System (CNS) Involvement: All patients will have a spinal tap to determine presence or absence of leukemia. Presence of leukemia is a poor prognostic sign.
  • Gender: Males tend to have a worse outcome than females following treatment.
  • Leukemia Morphology: It is important to determine whether the leukemia is of T or B-cell origin. Subtyping of patients with B-cell ALL is no longer considered important for determining risk status. These studies are performed by examining bone marrow obtained under local anesthesia by a needle aspiration from the hip bone.
  • Immunophenotyping: 80-85% of childhood ALL cases are classified as having precursor B-cell ALL. There are 3 subtypes of precursor B-cell ALL and three quarters of these are classified as common precursor B-cell ALL which denotes a good prognosis. Other subtypes have a worse prognosis.
  • Cytogenetics: Cytogenetics (evaluation of chromosomes) will be performed on leukemia cells obtained from the bone marrow. There are a multitude of different cytogenetic abnormalities associated with childhood ALL. Some cytogenetic abnormalities are associated with a poor prognosis but some are associated with a good prognosis.
  • After the initiation of treatment the rapidity of response as measured by bone marrow response on days 7 and 14 of treatment has prognostic significance.  Patients who have a slow or no clearing of leukemia blasts from the bone marrow by day 14 or 15 after initiation of treatment have a poor prognosis and are often assigned more aggressive treatments.12

Based on the above considerations patient are assigned a risk category. For example standard risk would be a child 1-9 years old, with a WBC less than 50,000, a B-cell phenotype, absence of CNS involvement, absence of adverse cytogenetic abnormalities such as the Philadelphia chromosome, and bone marrow clearing of leukemia on days 7 and 14 following initiation of treatment.

It is important to realize that prognostic groups are constantly changing as treatment regimens change, For example, more aggressive treatment regimens or allogeneic stem cell transplantation can overcome some adverse risk factors. In addition, newer genetic tests may be able to more accurately predict outcomes of children with ALL which would allow less treatment and less toxicity for children who do not need more intensive therapy. For instance, in one study gene profiling was used to identify eight types of pediatric ALL, representing 90% of all cases. These eight types have distinct biologic characteristics and predicted response to therapy.3,4 Gene profiling promises to be a significant method for identifying patients with aggressive or non-aggressive malignancies and should ultimately assist in disease management. These studies, however, require stored cells and it is important for all patients and clinicians to be aware of the importance of having tumor banks where future genetic studies can be correlated with clinical outcomes.

Understanding the prognosis of an individual child following treatment with conventional multi-drug post-remission therapy is essential in order to make informed decisions about proceeding with conventional treatment or pursuing more aggressive or new therapies.

Treatment of Average-Risk Childhood ALL

The majority of children will have what is termed “average-risk” ALL and will be treated with less intensive therapy than children with higher-risk disease. Attempts are made to reduce the doses of agents that are associated with more toxicities such as the anthracyclines which cause cardiac problems and alkylating agents which cause long-term side effects. One drug that is used in intermediate dosing in most protocols is methotrexate, and most protocols also rely heavily on asparaginase. One recent publication summarizes the trend of treating average-risk patients.5 Patients in this study were classified as lesser-risk by being between the ages of 1 and 9 years, having a WBC of less than 50,000, having trisomies 4 and 10 by DNA analysis, and no CNS leukemia. They all received induction therapy with vincristine, prednisone and asparaginase. They then received 6 courses of intravenous methotrexate and daily 6-mercaptopurine and intrathecal chemotherapy. CNS radiation was not administered. The total treatment duration was 2.5 years. The 6-year event-free survival was 87% and the overall survival was 97%. These authors suggested that “the great majority of children with less-risk B-lineage ALL are curable without agents with substantial late effects.”

Treatment of Higher-Risk Childhood ALL

Researchers affiliated with the Children’s Oncology Study Group have reported that “Stronger intensity but not prolonged duration of post induction intensification improved outcome for patients with higher-risk ALL”.6 This clinical trial was carried out in over 2000 children and adolescents with “higher-risk” ALL who had a rapid marrow response to induction therapy. This study compared standard post-induction intensification with either a longer duration of intensification or a more intensive intensification. These authors reported that stronger intensification improved 5-year event-free survival from 72% to 89% and overall survival from 83% to 89%. Increasing the duration of intensification did not improve outcomes. This study was carried out between 1996 and 2002 and required a large number of patients to detect relatively small differences in outcome. This study dramatically demonstrates the importance of national clinical trials to answer important treatment questions in childhood ALL.

Researchers from Europe have reported that patients with poor-risk ALL have an improved survival following allogeneic stem cell transplantation in first complete remission compared to continued chemotherapy.7 This study classified poor-risk patients as having failure to achieve a complete remission with first induction therapy; adverse cytogenetics; poor response to prednisone , T-cell phenotype, or white blood cell counts of 100,000 per cubic millimeter or more. This study was carried out between 1995 and 2000 in seven European centers. The basic design was to treat patients without a suitable related or unrelated stem cell donor with intensive chemotherapy and to transplant patients who had a donor after achieving a complete remission. In this study 280 children had no donor and received intensive chemotherapy while 77 had a donor and 55 actually received an allogeneic stem cell transplant according to protocol. The goal of the study was to perform the transplant in first remission but no later than five months from diagnosis. In the chemotherapy group, 43 patients ultimately received a stem cell transplant after relapse. Table 1 summarizes the main findings of this comparative study.

Table 1: Effect of allogeneic transplant after remission in poor-risk ALL patients

Allogeneic Transplant

Chemotherapy

Number of Patients

77

280

Relapse

34.2%

49.3%

5-year disease-free survival (DFS)

56.7%

40.6%

5-year overall survival

56.4%

50.1%

DFS-related donor

60%

DFS-unrelated donor

40%

These authors stated that the relative benefit of transplantation increased with increasing adverse risk factors. Thus, those children with the highest risk profile benefited the most from an early transplant. Eighteen of the 43 children who received a transplant after failure of chemotherapy became long-term survivors in complete remission. The results might have been more pronounced except for the fact that 18 of the 43 patients in the chemotherapy group who relapsed received a transplant.

Treatment of Specific Groups of High-Risk ALL Patients

T-Cell ALL: T-cell ALL comprises approximately 10-15% of children diagnosed with ALL. Historically, Patients with T-cell ALL had a worse prognosis compared to patients with B-cell ALL. However, recent results from the Dana-Farber Cancer Institute have reported a 5-year event-free survival rate of 75%, which is approximately 10% less than for B-cell ALL.8 Treatment consisted of a 4 or 5 drug induction regimen and consolidation therapy with doxorubicin, vincristine, corticosteroids, mercaptopurine and asparaginase.

Infant ALL: Infant ALL represents 2% to 4% of all cases of childhood ALL. Infant ALL is treated on separate protocols of the COG. In approximately 80% of cases there is a mutated MLL gene which connotes a worse prognosis. Event-free survival for infants with the MLL gene mutation is approximately 30-40% while results are somewhat better in cases where this gene is not mutated. A recent study from the Netherlands reported a 60% 5-year event-free survival among 482 infants with ALL treated between 1999 and 2005.9 Adverse prognostic features for poor survival were any mutation of the MLL gene, very high WBC, age younger than 6 months and a poor response to prednisone. However, a recent study from Japan showed that infants with ALL without a mutated MLL gene (germline status) had a survival of 95% showing the importance of this gene mutation.10 Allogeneic stem cell transplantation has been carried out in infants with ALL. However, a recent report from Children’s Oncology Group showed a 5-year event-free survival of only 20% for infants with ALL transplanted in first remission.11

Philadelphia Chromosome-Positive ALL: Approximately 3-5% of children with ALL have a cytogenetic defect called the Philadelphia chromosome, which is a translocation between chromosomes 9 and 22. The result of this genetic switching produces a protein called the Bcr-Abl tyrosine kinase. Patients who are Philadelphia chromosome-positive typically do not respond well to standard therapies and those who achieve a complete remission are advised to have an allogeneic stem cell transplant which results in a cure rate of approximately 65% compared to approximately 25% in patients who only receive chemotherapy.12 For more details ago to Allogeneic Stem Cell Transplantation.

Recently the tyrosine kinase inhibitor, Gleevec® (imatinib) has been found to profoundly affect the outcomes of children with Philadelphia chromosome-positive ALL. Researchers affiliated with Children’s Oncology Group (COG) have reported that the addition of Gleevec administered with induction, reinduction, and intensive maintenance chemotherapy improves outcomes of children with Philadelphia chromosome-positive ALL.13 Patients not receiving an allogeneic stem cell transplant had a one year event-free survival of 78% which was not inferior to those receiving an allogeneic stem cell transplant. These authors speculated that intensive Gleevec may be comparable to an allogeneic stem cell transplant. Gleevec clearly improved the outcome of children with PH+ ALL compared to historical controls. However, the data are too immature to conclude that intensive chemotherapy with Gleevec is equivalent to an allogeneic stem cell transplantation followed by Gleevec maintenance.

The Importance of Treating the Central Nervous System and Other Sanctuary Sites

Acute lymphoblastic leukemia cells spread into the central nervous system, testicles and other locations not easily reached with chemotherapy. These are often referred to as sanctuary sites. This is because many drugs are unable to penetrate into these areas and destroy the cancer cells. It is important to understand that it is easier to prevent leukemia recurrence than it is to treat leukemia after it recurs in these sites. Prevention of leukemia recurrence can be accomplished by injecting chemotherapy into the central nervous system or by treatment with radiation. This is referred to as central nervous system prophylaxis.

Intrathecal therapy is the term used to describe the injection of drugs into the central nervous system to prevent leukemia recurrence. It is performed by injecting the chemotherapy drugs methotrexate or cytarabine or both through a needle inserted into the spinal canal on several occasions. Patients not treated with intrathecal therapy have a rate of leukemia recurrence in the central nervous system of 20-50%. This has progressively decreased as more intensive treatments have been developed and the current risk of central nervous system recurrence is only 2-4% if chemotherapy is injected into the central nervous system according to the treatment plan. Treatment of the central nervous system is therefore standard. Radiation therapy can also be used to prevent leukemia in the central nervous system, but may be associated with more long-term side effects, especially in younger patients.

Strategies to Improve Post Remission Therapy for Acute Lymphoblastic Leukemia

While significant progress has been made in the treatment of leukemia, better treatment strategies are still needed. Future progress in the treatment of leukemia will result from continued participation in appropriate clinical studies. Currently, there are several areas of active exploration aimed at improving the treatment of leukemia.

Increased Intensity and Frequency of Post-Remission Treatments: The exact number and intensity of post-remission courses necessary to prevent leukemia recurrences without prohibitive side effects is still under investigation. Some patients with good-risk features could possibly benefit by a less intensive approach and others with bad-risk features could benefit by a more intensive treatment program.

Stem Cell Transplant: High-dose chemotherapy and autologous or allogeneic stem cell transplant are currently superior post-remission treatment options for many patients. To learn about new developments with these therapies, go to strategies to improve Allogeneic Stem Cell Transplant or Autologous Stem Cell Transplant.

New Drug Development: All new drugs for the treatment of patients with ALL are tested first in patients with relapsed or refractory disease. When they are found to be effective, they are then evaluated in remission induction regimens. This is more relevant for adults than children, since over 95% of children achieve a complete remission with existing treatment regimens.

New Tyrosine Kinase Inhibitors:

Sprycel® (dasatinib): Sprycel is a newly developed tyrosine kinase inhibitor that is more than 300 times more active than Gleevec for inhibition of Bcr-Abl (the abnormal protein produced by the Philadelphia chromosome). Sprycel is active in patients with Philadelphia chromosome-positive chronic myeloid leukemia that is resistant or intolerant to Gleevec, and can also produce complete cytogenetic remissions in patients with ALL who have failed Gleevec.14 In addition, Sprycel has been used to successfully treat patients with Philadelphia chromosome-positive leukemia that involves the central nervous system (CNS).15 One of the problems with Gleevec is that it does not penetrate the blood-brain barrier. Researchers involved in the current study stated that preclinical studies have shown that Sprycel is more effective than Gleevec for treatment of Philadelphia chromosome-positive leukemia that involves the CNS. They also report significant drug activity in 11 patients with Philadelphia chromosome-positive leukemia in the CNS. All patients responded, and seven of 11 had complete, long-lasting responses.

Tasigna® (nilotinib): Tasigna is an agent that inhibits the tyrosine kinase activity of the BRC-ABL oncogene in Philadelphia chromosome-positive leukemias. Tasigna is reported to have greater efficacy than Gleevec in Philadelphia-chromosome positive CML. Tasigna has reported activity in patients with refractory ALL but is still in Phase II testing and has yet to be studied in children.16

Monoclonal Antibodies

Monoclonal antibodies are proteins that can be made in the laboratory and are designed to recognize and bind to very specific sites on a cell. This binding action promotes anti-cancer benefits by eliminating the stimulating effects of growth factors and by stimulating the immune system to attack and kill the cancer cells to which the monoclonal antibody is bound. This approach delivers additional treatment specifically to cancer cells and avoids harming the normal cells. Some monoclonal antibodies can locate cancer cells and kill them directly. However, some antibodies have to be linked to a radioactive isotope or a toxin in order to kill cells and the antibodies essentially serve as a delivery system. Monoclonal antibodies can be administered alone or with chemotherapy and are being evaluated to determine whether they can improve cure rates.

Monoclonal antibodies directed at tumor antigens have made a major impact in the treatment of cancer over the past two decades. The major advantage of monoclonal antibody therapy is that the toxicities are not the same as for chemotherapy and when added to chemotherapy there is little increase in toxicity. However, there has been little progress in the development of monoclonal antibodies useful for the treatment of childhood ALL. However, this situation may be changing. Researchers from New York University have reported that epratuzumab, a humanized monoclonal antibody that targets CD22 antigen, is effective alone or in combination for the treatment of ALL.17 This study showed that epratuzumab could be safely added to chemotherapy with improved responses in patients with advanced ALL. A logical step would be to add epratuzumab to induction therapy.

There is emerging evidence that the anti-CD20 antibody Rituxan® (rituximab) has activity in some patients with ALL. A recent study has suggested that CD20 is upregulated in many cases of childhood ALL, making this disease a target for Rituxan.18 There are already reports of children with ALL responding to single-agent Rituxan or Rituxan in combination with chemotherapy.19 A study from MD Anderson Cancer Center has reported that the addition of Rituxan to intensive chemotherapy improved the outcomes of patients with ALL who were CD 20 positive.20 This is expected to be an area of intense research in the near future.

Other Drugs

Arranon® (nelarabine, 506U78): Arranon is a drug which has resulted in a 50% response rate in children with refractory T-cell ALL.21 This drug has now been incorporated into remission induction and consolidation therapy for children with T-cell ALL.22

Clolar® (clofarabine): Clorlar is a new drug that has been approved by the US Food and Drug Administration for the treatment of children who have failed two or more treatment regimens.23 This drug could be incorporated into remission induction and consolidation regimens in the future.

Detection of Minimal Residual Disease: Even after therapy, small amounts of cancer cells may be left in the bone marrow and may grow and cause a recurrence of the cancer. In the past, researchers have not been able to test for the presence of these remaining cancer cells and so could not precisely predict who was likely to have a leukemia recurrence and who was not. Now, emerging evidence suggests that a test called the polymerase chain reaction (PCR) is able to detect a small number of remaining leukemia cells—one among a million normal bone marrow cells—in patients with ALL-associated abnormal chromosomes. The PCR works by tracking the chromosomal abnormality associated with the cancer cells. These findings are important because they show that the PCR test is more sensitive in cancer detection than historically used tests and can therefore predict ALL patients that are likely to have a leukemia recurrence. For this reason, there is potential for using PCR results to determine which patients may need further treatment, perhaps with more intensive therapy and a stem cell transplant.

Supportive Care: Supportive care refers to treatments designed to prevent and control the side effects of cancer and its treatment. Side effects not only cause patients discomfort, but also may prevent the optimal delivery of therapy at its planned dose and schedule. In order to achieve optimal outcomes from treatment and improve quality of life, it is imperative that side effects resulting from cancer and its treatment are appropriately managed. For more information, go to Managing Side Effects.

References:


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2 Coustan-Smith E, Sancho J, Behm F, et al. Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood. 2002:100;52-58. Prepublished online April 17, 2002;100;52-58.

3 Mosquera-Caro M, Helman P, Veroff R, et al. Identification, Validation, and Cloning of a Novel Gene (OPAL 1) and Associated Genes Highly Predictive of Outcome in Pediatric Acute Lymphoblastic Leukemia Using Gene Expression Profiling. Blood 2004;102:4a, Abstract #1.

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