Treatment of Childhood Acute Lymphoblastic Leukemia

Cancer Connect - Treatment of Childhood Acute Lymphoblastic Leukemia

Childhood Acute Lymphoblastic Leukemia

Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/2018)

Acute lymphoblastic leukemia in children is a malignant disease or cancer of the blood characterized by the rapid uncontrolled growth of abnormal, immature white blood cells known as lymphoblasts. Acute lymphoblastic leukemia is the most common leukemia in children, with approximately 3,000 new patients diagnosed each year in the United States.

Progress in treating childhood ALL is attributed to risk-based therapy which was initiated three decades ago.[1] Risk-based therapy means administering more treatment to children at high risk of relapse and less therapy to those at lower risk to avoid long-term side effects. Therefore, it is important to understand what features constitute high, intermediate and low risk of relapse for planning successful treatment. According to recent analyses and computer modeling, current treatment strategies for children with ALL treated between 2005 and 2009 should result in a 10-year survival of approximately 88%.[2]

The following is a general overview of the treatment of childhood ALL. Treatment of adolescents and very young adults with ALL is often carried out using pediatric protocols because of data suggesting better outcomes for this group than when treatment is administered on adult protocols.[3] Treatment of adults with ALL is included in a separate section: Adult Acute Lymphoblastic Leukemia.

Prior to determining the optimal treatment of childhood ALL patients are assessed for risk factors to determine the current protocol that is most appropriate to direct treatment. 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 nine 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. 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 three 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, such as the Philadelphia chromosome, but some are associated with a good prognosis. One extra chromosome (trisomy) or higher than normal chromosome numbers (hyperdiploidy) is associated with an improved survival.
  • 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.[4],[5]

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 can overcome some adverse risk factors. In addition, newer genetic tests may be able to more accurately predict outcomes of children with ALL. In one study gene profiling was used to identify eight types of pediatric ALL, which represents 90% of all cases. These eight types have distinct biologic characteristics and predicted response to therapy.[6],[7] 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.

A recent review article summarizes the current strategies for drug treatment of children with ALL.[8] The treatment of childhood ALL is carried out in two phases. The initial treatment phase is called remission induction and the goal of remission induction therapy is to achieve a complete remission or disappearance of all detectable leukemia cells in the peripheral blood and bone marrow. After a complete remission is achieved, the second phase of treatment, called post-remission therapy, begins. Post-remission therapy is necessary because despite achieving a complete remission of leukemia with induction treatment, hidden undetectable leukemia cells still exist and the leukemia will return without additional post-remission therapy. Post-remission therapy is often referred to as consolidation. The intensity of post-remission therapy is dictated by risk factors for relapse as outlined above.

Remission Induction

Researchers have learned that the best way to cure children with ALL is to administer large doses of several chemotherapeutic drugs over a short period of time. The concept is to kill leukemia cells quickly before resistance to the drugs occurs. Therapy is divided into two phases, remission induction and post-remission therapy. Remission induction chemotherapy is administered to produce a complete remission (complete disappearance of detectable leukemia by microscopic examination) in the bone marrow, peripheral blood and central nervous system (CNS). A complete remission is said to occur when less than 5% of leukemia “blasts” remain in the bone marrow, blood counts have returned to normal, and there is no leukemia elsewhere in the body. Currently, over 95% of children with ALL will achieve a complete remission following initial multiagent chemotherapy treatment. The definition of complete remission, however, is changing; detection of minimal residual disease (MRD) by very sensitive tests such as reverse transcription polymerase chain reaction (RT-PCR) and cytogenetic analysis is becoming an important part of determining whether or not patients achieve a true complete remission. This is because patients who have MRD are at high risk of recurrent disease.

Most children receive treatment through government sponsored clinical trials on protocols designed by the Children’s Oncology Group. These studies frequently evaluate more intensive therapy for children at high risk of treatment failure and less intensive therapy for better risk patients. It is important that children be treated on these clinical studies whenever possible in order to ensure that all of the therapy is correctly administered and to further the knowledge of treatment of childhood ALL.

Remission induction therapy for standard-risk children with ALL currently consists of administering three drugs: Oncovin® (vincristine), prednisone or dexamethasone, and Elspar® (L-asparaginase) or Oncaspar® (PEG-L-asparaginase). Elspar and Oncospar are made from E. Coli and either can be used in remission induction. However, current COG protocols use Oncaspar during induction for all children with ALL.[2] Patients with an allergic reaction to Oncaspar or Elspar are switched to Erwinia L-asparaginase. Children with ALL also receive drugs such as methotrexate injected into the spinal fluid to prevent relapse in the CNS. The complete remission rate is greater than 95% with this therapy.[3]

Patients who are deemed at high or very high risk of relapse with standard therapy often receive four or more drugs in the induction regimen. This more intensive induction therapy is more toxic and has more side effects. Such therapy could include an anthracycline such as Cerubidine® (daunorubicin) or Adriamycin® (doxorubicin), Cytoxan® (cyclophosphamide), VePesid® (etoposide) or Cytosar® (cytarabine, ara-C).

Children with Philadelphia chromosome-positive ALL usually receive Gleevec® (imatinib) in the induction regimen. 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 childhood ALL.[4]

Induction therapy lasts for approximately 4-6 weeks. Following remission induction, patients typically require 2-3 weeks for bone marrow blood cell production to recover. During this time, patients often require blood and platelet transfusions to maintain red blood cell and platelet levels. In order to reduce the risk of infection, antibiotics and blood cell growth factors that stimulate the bone marrow to produce normal white blood cells (neutrophils) are often given. The white blood cell growth factors Neupogen® (filgrastim) and Neulasta® (pegfilgrastim) have been demonstrated in clinical studies to reduce the severity of neutropenia and shorten hospital stays.[5] Current practice would suggest that the prophylactic use of Neupogen and Neulasta is most effective when administered to poor-risk patients receiving an intensive induction regimen and reserving these agents in good-risk patients receiving less intensive therapy for only those who develop prolonged neutropenia.

After blood counts recover following remission induction chemotherapy, a bone marrow examination is repeated to see if a remission has been achieved. If a complete remission is achieved and no further therapy given, over 90% of patients will have a recurrence of leukemia in weeks to months. To prevent recurrence of leukemia, post-remission therapy is initiated immediately after recovery from induction therapy. These treatments are given as close together as possible. The more intensive the chemotherapy and the closer together the courses of therapy are given, the less chance the leukemia has of recurring. It is very important to understand that lower doses of drugs do not work as well as higher doses of drugs.

For patients not in remission, a second remission induction course of treatment can be given immediately or patients can proceed directly to stem cell transplantation, which is currently the most effective way to cure patients failing to achieve a complete remission with initial treatment.

Strategies to Improve Remission Induction

The development of intensive multi-agent chemotherapy induction regimens, improvements in supportive care and patient and physician participation in clinical studies have resulted in steady progress in the safety of induction therapy and higher response and cure rates. The following strategies are currently being evaluated alone or in combination for the purpose of improving the treatment of ALL.

Increased Dose Intensity: Because higher doses of chemotherapy kill more leukemia cells than lower doses, many doctors have advocated increasing the dose or dose intensity of chemotherapy drugs as a way to improve remission and cure rates of patients with ALL. Increasing the dose intensity can be accomplished by increasing the number of doses of drugs in remission induction therapy, increasing the dose intensity of post remission therapy, or by administering very high dose chemotherapy supported with stem cell transplantation as part of the overall treatment strategy. While some investigators have focused on increasing the dose intensity of remission induction therapy, others have focused on increasing the intensity of post remission therapy.

Some studies have suggested that increasing the intensity of remission induction therapy can translate into improved outcomes for patients with ALL. Increasing dose intensity is also associated with increased side effects and should be reserved for patients with a poor prognosis.

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.[6] In addition, Sprycel has been used to successfully treat patients with Philadelphia chromosome-positive leukemia that involves the central nervous system (CNS).[7] 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.[8]

Monoclonal Antibody Therapy

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.[9] This study showed that epratuzumab could be safely added to chemotherapy with improved responses in patients with advanced ALL. The Childrens Oncology Group plans to add epratuzumab for induction in children with high-risk ALL.

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.[10] There are already reports of children with ALL responding to single-agent Rituxan or Rituxan in combination with chemotherapy.[11] A study from MD Anderson Cancer Center has reported that the addition of Rituxan to intensive chemotherapy improved the outcomes of adult patients with ALL who were CD20-positive.[12] 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.[13] This drug has now been incorporated into remission induction and consolidation therapy for children with T-cell ALL.[14]

Clolar® (clofarabine)*:* Clolar is a new drug that has been approved by the US Food and Drug Administration for the treatment of children who relapsed after primary therapy.[15] This agent might be incorporated into induction regimens in poor-risk patients in the future.

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.

Strategies to improve treatment of patients who fail remission induction are also discussed in the section on Allogeneic Stem Cell transplantation.

Post-Remission Treatment

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.[1],[2]

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

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.

Post Remission Therapy

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:

[1] Trigg ME, Sather HN, Reaman GH, Ten year survival of children with acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Leukemia Lymphoma 2008;49:1142-1154.

[2] Pute D, Gondos A, Brenner H, Trends in 5- and 10-year survival after diagnosis with childhood hematologic malignancies in the United States, 1990-2004. Journal of the National Cancer Institute 2008; early on-line publication on September 9.

[3] Boissel N, Auclerc M-F, Lhéritier V, et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. Journal of Clinical Oncology. 2003;21:774-780.

[4] Sandlund J, Harrison P, Rivera G, et al. Persistence of lymphoblasts in bone marrow on day 15 and days 22 to 25 of remission induction predicts a dismal treatment outcome in children with acute lymphoblastic leukemia. Blood. 2002:100;43-47.

[5] 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; DOI 10.1182/blood-2002-01-0006.

[6] 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.

[7] Fine B, Stanulla M, Schrappe M, et al. Gene Expression Patterns Associated with Recurrent Chromosomal Translocations in Acute Lymphoblastic Leukemia. Blood 2004;103;1043-1049.

[8] Pui C-H, Evans WE. Treatment of Acute Lymphoblastic Leukemia. New England Journal of Medicine2006;354:166-178.

[1] Boissel N, Auclerc M-F, Lhéritier V, et al. Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. Journal of Clinical Oncology. 2003;21:774-780.

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[8] Piccaluga PP, Paolini S, Marinelli G, et al. Tyrosine kinase inhibitors for Philadelphia chromosome positive adult acute lymphoblastic leukemia. Cancer 2007;110:1178-1186.

[9] Raetz EA, Cairo MS, Borowitz MJ, et al. Chemoimmunotherapy reinduction with epratuzumab with acute lymphoblastic leukemia in marrow relapse: a Children’s Oncology Pilot Study. Journal of Clinical Oncology. 2008;26:3756-3762.

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[11] Gokbuget N and Hoelzer D, Treatment with monoclonal antibodies in acute lymphoblastic leukemia: current knowledge and future prospects. Annals of Hematology 2004;83:201-205.

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[14] Dunsmore K, Devidas M, Borowitz MJ, et al.: Nelarabine can be safely incorporated into an intensive, multiagent chemotherapy regimen for the treatment of T-cell acute lymphocytic leukemia (ALL) in children: a report of the Children’s Oncology Group (COG) AALL00P2 protocol for T-cell leukemia. Blood 2006;108 abstract 1864.

[15] Kearns P, Michel G, Neiken B, et al. BIOV-111 a European phase II trial of aClorarabine (Evoltra® in refractory and relapsed childhood acute lymphoblastic leukemia. Blood 2006;108: abstract number 1864.

[1] Sandlund J, Harrison P, Rivera G, et al. Persistence of lymphoblasts in bone marrow on day 15 and days 22 to 25 of remission induction predicts a dismal treatment outcome in children with acute lymphoblastic leukemia. Blood. 2002:100;43-47.

[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.

[4] Fine B, Stanulla M, Schrappe M, et al. Gene Expression Patterns Associated with Recurrent Chromosomal Translocations in Acute Lymphoblastic Leukemia. Blood 2004;103;1043-1049.

[5] Chauvenet AR, Martin Pl, Devidas M, et al. Antimetabolite therapy for lesser-risk B-bineage acute lymphoblastic leukemia of childhood: a report from Children’s Oncology Group Study P9201. Blood2007;110:1105-1111.

[6] Seibel NL, Steinherz PG, Sather HN, et al. Early postinduction intensification therapy improves survival for children and asdolescents with high-risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Journal of Clinical Oncology 2008;111:2548-2555.

[7] Balduzzi A, Valsecchi MG, Uderzo C, et al. Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukemia in first complete remission: comparison by genetic randomization in an international prospective study. Lancet 2005; Aug 20-26;366(9486):635-42.

[8] Goldberg JM, Silverman LB, Levy DE, et al. Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. Journal of Clinical Oncology2003; 21:3616-3622.

[9] Pieters R, Schrappe M, De Lorenzo P, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomized trial. Lancet 2007;370:240-250.

[10] Nagayama J, Tomizawa D, Koh K, et al. Infants with acute lymphoblasic leukemia and a germline MLL gene are highly curable with use of chemotherapy alone: results from the Japan Infant Leukemia Study Group. Blood 2006;107:4663-4665.

[11] Satwani P, Sather H, Ozkayak F, et al. Allogeneic bone marrow transplantation in first remission for children with ultra-high-risk features of actue lymphoblastic leukiemia: A Children’s Oncology Group study.report. Biology of Blood and Marrow Transplantation 2007;13:218-227.

[12] Satwani P, Sather H, Ozkayak F, et al. Allogeneic bone marrow transplantation in first remission for children with ultra-high-risk features of acute lymphoblastic leukemia: A Children;s Oncology Group study report. Biology of Blood and Marrow Transplantation. 2007;13:218-227.

[13] Kirk R, Schultz W, Bowman P, et al. Improved early event-free survival (EFS) in children with Philadelphia chromosome-positive (PH+) acute lymphoblastic leukemia (ALL) with intensive imatinib in combination with high dose chemotherapy: Children’s Oncology Group (GOG) Study:AALL0031. . American Society of Hematology 2007. Blood 2007;110:abstract number 4.

[14] Brave M, Goodman V, Kaminskas E, et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia resistant or intolerant of imatinib mesylate. Clinical Cancer Research 2008;14:252-369.

[15] Porkka K, Koskenvesa P, Lundan T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome positive leukemia. Blood 2008;112:1005-1012.

[16] Piccaluga PP, Paolini S, Marinelli G, et al. Tyrosine kinase inhibitors for Philadelphia chromosome positive adult acute lymphoblastic leukemia. Cancer 2007;110:1178-1186.

[17] Raetz EA, Cairo MS, Borowitz MJ, et al. Chemoimmunotherapy reinduction with epratuzumab with acute lymphoblastic leukemia in marrow relapse: a Children’s Oncology Pilot Study. Journal of Clinical Oncology. 2008;26:3756-3762.

[18] Dworzk MN, Schumich A, Printz D, et al. CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immumotherapy. Blood 2008;Epub on September 9.

[19] Gokbuget N and Hoelzer D, Treatment with monoclonal antibodies in acute lymphoblastic leukemia: current knowledge and future prospects. Annals of Hematology 2004;83:201-205.

[20] Thomas DA, Faderl S, O, Brien et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer2006;106:1569-1580.

[21] Berg SL, Blaney SM, Devidas M, et al. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children’s Oncology Group. Journal of Clinical Oncology 2005;20:3376-3382.

[22] Dunsmore K, Devidas M, Borowitz MJ, et al.: Nelarabine can be safely incorporated into an intensive, multiagent chemotherapy regimen for the treatment of T-cell acute lymphocytic leukemia (ALL) in children: a report of the Children’s Oncology Group (COG) AALL00P2 protocol for T-cell leukemia. Blood 2006;108 abstract 1864.

[23] Kearns P, Michel G, Neiken B, et al. BIOV-111 a European phase II trial of aClorarabine (Evoltra® in refractory and relapsed childhood acute lymphoblastic leukemia. Blood 2006;108: abstract number 1864.

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