Remission Induction

Overview

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.

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 using adult protocols.1 Treatment of most adults with ALL is included in a separate section: Adult Acute Lymphoblastic Leukemia.

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. To learn more about treatment of patients failing to achieve a complete remission with initial treatment, go to Refractory ALL.

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.

References:


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2 Avramis VI, Sencer S, Periclou AP, et al.: A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood 2002;99: 1986-94.

3 Pui C-H, Evans WE. Treatment of Acute Lymphoblastic Leukemia. New England Journal of Medicine 2006;354:166-178.

4 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.

5 Pui Ch, Boyett JM, Hughes WT, et al. Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. New England Journal of Medicine 1997;336:1781-1787.

6 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.

7 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.

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.

10 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 immunotherapy. Blood 2008;Epub on September 9.

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.

12 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. Cancer 2006;106:1569-1580.

13 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.

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.