Researchers have learned that the best way to cure patients with adult 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) in the bone marrow and other sites. A complete remission is said to occur when less than 5% of leukemia “blasts” remain in the bone marrow, blood cell counts have returned to normal, and there is no ALL elsewhere in the body. Currently, 90% of adults with ALL will achieve a complete remission following initial multiagent chemotherapy treatment.
Remission induction for adults consists of multiagent chemotherapy and injection of chemotherapy into the spinal fluid (intrathecal injection) to prevent relapses in the central nervous system (CNS). Current remission induction therapy involves the use of 4-5 different drugs. Protocols sponsored by the National Cancer Institute are carried out by cooperative groups in the US. These groups have protocols for all phases of treatment of ALL and include:
- Cancer and Leukemia Group B (CALGB): http://www.calgb.org/
- Eastern Cooperative Oncology Group (ECOG): http://www.ecog.org/
- Southwest Oncology Group (SWOG): http://www.swog.org/
Information about National Cancer Institute-sponsored protocols for ALL can be obtained at cancer.gov.
Standard remission induction therapy currently consists of administering chemotherapy drugs over approximately one month. 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, shorten hospital stays, and decrease episodes of febrile neutropenia.1,2
Drugs used during remission induction usually include Oncovin® (vincristine), Elspar® (L-asparaginase) or Oncaspar® (peg-L-asparaginase),3 and an anthracycline such as Adriamycin® (doxorubicin). 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 Cytoxan® (cyclophosphamide), VePesid® (etoposide) or Cytosar® (cytarabine, ara-C). Strategies for treating adult ALL have been recently reviewed in the New England Journal of Medicine.4
Researchers from the University of California at San Francisco have reported a 93% remission induction rate following remission induction treatment with Cerubidine® (daunorubicin), Oncovin, prednisone, and Elspar.5
Hyper-CVAD: An intensive multiagent regimen, hyper-CVAD, has been developed at the MD Anderson Cancer Center for the treatment of adult ALL.6 This regimen is administered in eight courses and alternates Cytoxan, Oncovin, Adriamycin, and dexamethasone with high doses of methotrexate and Cytosar followed by maintenance with 6-mercaptopurine, Oncovin, methotrexate and prednisone. This is a more aggressive regimen than others previously studied and has different effects depending on age and co-morbid conditions in patients with ALL. Following remission induction with hyper-CVAD the complete remission rate in older patients was 84% compared to 92% in younger patients. The 84% remission rate was higher than the 59% previously observed in older patients with less intensive regimens. However, the mortality rate during remission induction was 10% for older patients compared 2% for younger patients.
Specific Subtypes of Adult ALL
Philadelphia Chromosome-Positive ALL
Up to 40% of adults with ALL have the Philadelphia chromosome in their leukemic cells which connotes an adverse prognosis. This abnormality increases with age, making the treatment of older patients difficult. Adults with Philadelphia chromosome-positive ALL usually receive Gleevec® (imatinib), a tyrosine kinase inhibitor, in the induction regimen. Gleevec is specific for this disease and fortunately is not associated with the same side effects as chemotherapy drugs. Current treatment of adult patients with Philadelphia chromosome-positive ALL is aggressive multi-agent chemotherapy and Gleevec. The goal of therapy in younger individuals is to induce a complete remission prior to allogeneic stem cell transplantation. For patients not suitable for allogeneic transplantation due to age or significant health problems, long-term maintenance therapy with Gleevec is administered.
Researchers from France have reported that Gleevec and methylprednisone alternated with chemotherapy improves outcomes of elderly patients with Philadelphia chromosome-positive ALL.7 This study included patients who were 55 years of age or older. A complete remission was achieved in 90% of patients. These results are significantly better than for patients not treated with Gleevec.
Researchers from the MD Anderson Cancer have treated 54 patients with Philadelphia chromosome-positive ALL with hyper-CVAD (described above) and Gleevec.8 All patients received Gleevec for the first 14 days of induction and continuously through courses 2-8 with indefinite maintenance. The complete remission rate was 93% and the complete molecular complete remission rate was 52%. Patients who have no detectable minimal residual disease by molecular tests are more likely to be cured than patients who have detectable minimal residual disease.
Multiagent chemotherapy produces remissions in approximately 40% of patients but most patients die of progressive disease.9 Patients with T-cell leukemia should be treated on innovative protocols sponsored by the National Cancer Institute and cooperative oncology groups aimed at improving outcomes.
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 adults 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 patients should directly inquire about these side effects.
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
Gleevec is a tyrosine kinase inhibitor that was designed specifically for the treatment of leukemia associated with the Philadelphia chromosome abnormality. This drug has revolutionized the treatment of Philadelphia chromosome positive ALL. However, drug resistance occurs and patients with ALL can fail treatment. Therefore, there is considerable research into the development of new tyrosine kinase inhibitors that can overcome resistance to Gleevec. There are two drugs currently approved by the US Food and Drug Administration (FDA) for treating adult ALL patients that have failed Gleevec: Sprycel® (dasatinib) and Tasigna® (nilotinib). There are other tyrosine kinase inhibitors in the drug development pipeline that have not yet been approved by the FDA, including bosutinib (SK1606).
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 can produce complete cytogenetic remissions in patients with ALL who have failed Gleevec.10,11 In addition, Sprycel is more effective than Gleevec for the treatment of Philadelphia chromosome-positive ALL that involves the central nervous system (CNS).12
Researchers from M.D. Anderson Cancer Center have reported the outcomes of newly diagnosed patients with Philadelphia chromosome-positive ALL treated with hyper-CVAD (see description of regimen above) and Sprycel.13 In this study, patients were treated with 14 days of Sprycel with each cycle of hyper-CVAD followed by indefinite maintenance with Sprycel. The complete remission rate was 85% and the complete cytogenetic remission rate was 70%.
Tasigna® (nilotinib): Tasigna is another tyrosine kinase inhibitor which has more potency than Gleevec. Tasigna produces significant remissions in patients with adult ALL who have failed Gleevec.14,15
Bosutinib (SK1606): Bosutinib is a drug that is still in phase I-II testing but it is also more potent than Gleevec. Preliminary studies show that this agent has significant activity in adults with ALL who are refractory to Gleevec.16
Taken together it appears that there will be many new drugs for the treatment of Philadelphia chromosome-positive adult ALL which may make allogeneic stem cell transplantation less of a necessity.
Monoclonal Antibody Therapy
Monoclonal antibodies directed at tumor antigens (specific components of cancer cells) 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 side effects. There has been little progress in the development of monoclonal antibodies useful for the treatment of adult 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. The Children’s Oncology Group plans to add epratuzumab for induction in children with high-risk ALL.
There is emerging evidence that the widely used 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 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 adult patients with ALL who were CD20-positive.20 This is expected to be an area of intense research in the near future.
Monoclonal Antibody Conjugated with Toxins
Mylotarg® (gemtuzumab ozogamicin) is an antibody to CD33 that is conjugated (joined) with a cytotoxic (cell-killing) antitumor antibiotic. This antibody conjugate is approved by the U.S. FDA for the treatment of patients with acute myeloid leukemia (AML) who have failed other therapies. A small fraction of patients with ALL also have leukemia cells that are CD33-positive, and Mylotarg has been effective in treating children with CD33-positive ALL.21 Experience with treating adult patients with CD33-positive ALL is limited.
Purine Nuleotide Analogs
Three new drugs that are analogs of the commonly used chemotherapy drug 6-mercaptopurine are currently under investigation for the treatment of ALL: Clolar® (clofarabine), Arranon® (nelarabine, 506U78), and forodesine. Clolar and Arranon have been approved by the FDA for treatment of refractory patients with ALL.22
- Arranon: Arranon is a drug which has resulted in a 50% response rate in children with refractory T-cell ALL.23 This drug has now been incorporated into remission induction and consolidation therapy for children with T-cell ALL.24
- Clolar: Clolar is a new drug that has been primarily evaluated in children with ALL who relapsed after primary therapy.25 This agent might be incorporated into induction regimens in poor risk patients in the future.
- Forodesine: Forodesine is the most recent purine antagonist still in Phase I-II testing. However it has shown promise for the treatment of both T-cell and B-cell ALL.
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.
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2 Lane SW, Crawford J, Kenealy M et al. Safety and efficacy of pegfilgrastim compared to granulocyte colony stimulating factor (G-CSF) supporting dose-intensive, rapidly cycling anti-metabolite containing chemotherapy regimen (Hyper-CVAD) for lymphoid malignancy. Leukemia Lymphoma 2006;47:1813-1817.
3 Douer D, Yampolsky H, Watkins K, et al. Pharmacokinetics, and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia. Blood. 2007; 109:2744-2750.
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6 O’Brien S, Thomas DA, Ravandi F, et al. Results of the hypofractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone regimen in elderly patients with acute lymphoblastic leukemia. Cancer 2008;early on-line publication on August 20.
7 Delannoy A, Delabesse E, Lheritier V, et al. Imatinib and methylprednisolone alternated with chemotherapy improve outcomes of elderly patients with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia: results of the GRAALL AFR09 study. Leukemia. 2006;20:1526-1532.
8 Thomas DA, Kantarjian HM, Cortes JE, et al. Outcome after frontline therapy with the hyper-CVAD and imatinib mesylate regimen for adults with de novo or minimally treated Philadelphia (PH) positive acute lymphoblastic leukemia (ALL). Journal of Clinical Oncology. 2008;26:abstract 7019.
9 Hermine O, Wattel E, Grssain A, et al. Adult T cell leukaemia: a review of established and new treatments. BioDrugs 10:447-462.
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11 Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New England Journal of Medicine. 2006;354:2531-2541.
12 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.
13 Ravandi F, Faderl S, Thoma DA, et al. Phase II study of combination of the hyper CVAD regimen with dasatinib in patients (pts) with newly diagnosed Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Journal of Clinical Oncology. 2008;26:abstract 7020.
14 Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.The New England Journal of Medicine. 2006;354:2542-2551.
15 Piccaluga PP, Paolini S, Marinelli G, et al. Tyrosine kinase inhibitors for Philadelphia chromosome positive adult acute lymphoblastic leukemia. Cancer 2007;110:1178-1186.
16 Gambacorti-Passerini C, Blummedorf T, Kantarjian H, et al. Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or AML who failed imatinib. Proceedings from the American Society of Clinical Oncology Conference. 2008 Chicago/IL. Abstract # 7006.
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 immunotherapy. 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. Cancer 2006;106:1569-1580.
21 Chevallier P, Mahe B, Garand R, et al. Combination of chemotherapy and gemtuzumab ozogamicin in adult Philadelphia positive acute lymphoblastic leukemia patient harboring CD33 expression. International Journal of Hematology 2008:209-211.
22 Larson RA. Three new drugs for acute lymphoblastic leukemia: nelarabine, clofarabine, and forodesine. Seminars in Oncology 2007;34:513-520.
23 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.
24 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,
25 Kearns P, Michel G, Neiken B, et al. BIOV-111 a European phase II trial of Clorarabine (Evoltra® in refractory and relapsed childhood acute lymphoblastic leukemia. Blood 2006;108: abstract number 1864.