Treatment of Adult Acute Lymphoblastic Leukemia

Cancer Connect - Treatment of Adult Acute Lymphoblastic Leukemia

Adult Acute Lymphoblastic Leukemia

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

Adult ALL is a malignant disease or cancer of the blood characterized by the rapid uncontrolled growth of abnormal, immature white blood cells known as lymphoblasts. There are approximately 5,000 new cases of Adult ALL each year in the US with approximately 1500 deaths.

There has been significant progress in treating adult ALL over the past several decades and currently 60-80% of patients will achieve a complete remission following combination chemotherapy induction and 30-40% will become long-term survivors and possibly cured.

The following is a general overview of the treatment of adult ALL. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.

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.[1] Treatment of children with ALL, including adolescents and young adults, is included in a separate section. Go to: Childhood Acute Lymphoblastic Leukemia.

In order to understand the best treatment options available for adult ALL, patients should know whether they have a B-cell or T-cell leukemia, the classification or histologic subtype (L1-L3) of leukemia, the initial white blood cell count, and the results of analyses of chromosomes by cytogenetic examination. These are all tests that are performed on a sample obtained from the bone marrow.

Adult ALL is frequently associated with abnormal chromosomes of the leukemia cells. Knowing the specific chromosomal abnormalities associated with your leukemia can be important for treatment planning as some are associated with a relatively good prognosis and others with a worse-than-average prognosis with standard treatment. More recently, molecular testing has been found to be more accurate than cytogenetics in detecting abnormalities that affect outcome.[2] It is important to identify patients with Philadelphia chromosome-positive ALL because there are drugs which are only effective for this subset of adults with ALL. However, this subset of patients represents up to 40% of all elderly patients with ALL.

The treatment of adult ALL occurs in two phases. The initial treatment phase is called remission induction. The goal of remission induction therapy is to achieve a complete remission or disappearance of all detectable leukemia cells in bone marrow, peripheral blood and other sites such as the testes and central nervous system (CNS). 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.

Remission Induction

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.

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.

T-Cell Leukemia

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.

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 with standard intensive post-remission therapy can now cure 25-35% of adults with ALL. It is important to understand what determines the success or failure of treatment in order to ensure the best outcome for an individual patient. Standard post-remission therapy in adults consists of treatment with more than one cycle of multi-agent intensive chemotherapy, or stem cell transplant combined with preventive treatment (prophylaxis) of the central nervous system and prolonged low-dose “maintenance” chemotherapy for 1-3 years.

Risk Factors

The major determinants of the outcome of post-remission therapy among adults with ALL are the presence of adverse risk factors and the intensity of post-remission therapy. Understanding your prognosis 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. Increasing age and the presence of significant other diseases are among the most important risk factors for a poor outcome. This is because elderly, ill patients do not tolerate intensive treatment regimens without significant toxicities. Younger adults with adverse risk factors may wish to perform an early search for an allogeneic stem cell donor in case chemotherapy treatment is a failure.

ALL is associated with a genetic or chromosomal abnormality in over 50% of adult patients with ALL. The most common chromosomal abnormality in adults is the Philadelphia chromosome, which occurs in up to 40% of patients and increases in frequency with age. Adults with the Philadelphia chromosome abnormality have also historically experienced an extremely poor outcome with conventional multi-drug post-remission therapy. In several clinical studies, 90%-100% of patients have been reported to experience a recurrence of leukemia following treatment with conventional post-remission therapy.

Low- and Intermediate-Risk ALL

Historically, adult patients with low- and intermediate-risk ALL have had a 25-35% cure rate with standard chemotherapy. This treatment includes remission induction, followed by intensive consolidation and maintenance therapy for 2-3 years. Treatment has also included cranial radiation to prevent relapses in the central nervous system (CNS). Most regimens have included high doses of anthracyclines such as Adriamycin® (doxorubicin) or Cerubidine® (daunorubicin). However, cranial radiation and high-dose anthracycline treatment can be associated with severe long-term side effects. Thus, there have been attempts to develop curative regimens with fewer long-term side effects.

At the University of California at San Francisco, researchers have focused their attention on improving the outcomes of adult patients with ALL by decreasing the total amount of anthracyclines administered and omitting cranial radiation.[1] The regimen tested included a four-drug induction regimen of Oncovin® (vincristine), Cerubidine, Elspar® (L-asparaginase) and prednisone. This produced a complete response rate of 93%. After remission induction patients received cyclical therapy with high-dose Cytosar® (cytarabine)/ VePesid® (etoposide) alternated with high-dose methotrexate/6-mercaptopurin and Cerubidine, Oncovin, prednisone, and Elspar®.

Maintenance chemotherapy with oral methotrexate and 6-mercaptopurine was continued for 30 months. CNS prophylaxis was given with intrathecal methotrexate in addition to the systemic chemotherapy indicated above. These researchers treated 84 patients age 60 or younger and 93% achieved complete remission. The 5-year event-free survival of all patients who achieved a remission was 52%. Thirteen high risk patients received a stem cell transplant and 7 survive in complete remission. Nine high-risk patients did not receive a transplant and all have died.

Allogeneic Stem Cell Transplantation in First Complete Remission

Utilizing allogeneic stem cell transplantation for post-remission therapy results in cure for up to 50% of young adults if they have a suitable stem cell donor and are transplanted after remission induction chemotherapy. An allogeneic stem cell transplant is a procedure that involves the infusion of donor stem cells into a patient in order to rescue low levels of blood cells caused by high-dose treatment. Adult patients with adverse risk factors may wish to consider treatment with allogeneic stem cell transplant and have an early donor search for an allogeneic stem cell donor performed. It is important for patients with adverse risk factors to identify a suitable allogeneic stem cell donor at the time of diagnosis. To learn more go to Allogeneic Stem Cell Transplant.

A combined US (Eastern Cooperative Oncology Group) and UK study has confirmed that an allogeneic stem cell transplant in first complete remission is the best option for patients with standard- and high-risk ALL who were 65 years of age or younger.[2] Patients with Philadelphia chromosome-positive ALL were excluded from this study. This study enrolled 2000 patients with standard- and high-risk ALL over a 13-year period. Patients were offered an allogeneic stem cell transplant in first remission if a donor was available. If no donor was available, patients were randomly allocated to receive prolonged chemotherapy (2.5 years) or an autologous stem cell transplant. The following were the main findings of this study:

  • The complete remission rate for the entire group was 91%
  • The overall 5-year survival for the entire group was 38%
  • Patients in the allogeneic transplant group had a survival at 5 years of 63% compared to 51% for those without a donor.
  • The relapse rate for patients in the transplant group was 39% compared to 62% without a donor.
  • Treatment-related mortality was higher in the allogeneic transplant group especially in those over the age of 35 years.
  • Survival of patients on prolonged chemotherapy was 42% compared to 33% for those randomized to receive an autologous stem cell transplantation.
  • This overall advantage for transplantation was not seen in high-risk patients, defined as age greater than 35 years or high WBC (>30,000 for B-lineage or >100,000 for T-cell lineage).

These authors concluded that allogeneic transplantation in first remission offered the best treatment for standard-risk adult ALL and that there was no advantage to an autologous transplant over consolidation and maintenance chemotherapy.

Only a minority of patients with adult ALL will have a related donor and must resort to using an unrelated donor or umbilical cord blood. Researchers affiliated with the European Bone Marrow Transplant (EBMT) Registry have reported that, for adults with ALL in first remission, allogeneic stem cell transplants from unrelated donors result in similar outcomes to those observed following related allogeneic stem cell transplants.[3] These authors reported that the disease-free survival for patients with ALL in first complete remission was 45% following a related donor transplant and 42% following an unrelated donor transplant.

Consolidation and Maintenance Therapy in Specific Subtypes of ALL

Philadelphia Chromosome-Positive ALL

Prior to the development of Gleevec® (imatinib), adult patients under the age of 55 or 65 with no significant co-morbitities were advised to have an allogeneic stem cell transplant in first remission. In the pre-Gleevec era a large French study reported a 3-year survival of patients receiving an allogeneic stem cell transplant of 37%, compared to 12% for patients receiving continued chemotherapy without a transplant.[4] Currently all patients with Philadelphia chromosome-positive ALL receive Gleevec indefinitely.

The current approach to post-remission therapy of patients with adult ALL is exemplified by a recent study from the MD Anderson Cancer. These researchers treated 54 patients with Philadelphia chromosome positive ALL with a regimen called hyper-CVAD. 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.[5] All patients received Gleevec for the first 14 days of induction and continuously through courses 2-8 with indefinite maintenance. The complete response rate was 93% and the molecular complete remission rate was 52%. Sixteen patients in this study underwent allogeneic stem cell transplantation. Overall survival rates were 70% for transplant recipients and 54% for non-transplant recipients. The authors compared the results of hyper CVAD with and without Gleevec and concluded that Gleevec improved disease-free survival from 14% to 62% and overall survival from 15% to 55%.

Older Patients with ALL

Hyper-CVAD: A common multiagent regimen developed at the MD Anderson Cancer Center for the treatment of adult ALL is called hyper-CVAD.[6] This regimen includes Cytoxan, Oncovin, Adriamycin, and dexamethasone combined with high doses of methotrexate and Cytosar followed by maintenance with 6-mercaptopurine, Oncovin, methotrexate and prednisone. This is a more aggressive regimen than usual and has different effects depending on age. Following remission induction with hyper-CVAD the complete remission rate in older patients was 84% compared to 92% in younger patients. However, the mortality rate during remission induction was 10% for older patients compared 2% for younger patients. In addition 34% of older patients died, usually of infections, while in first complete remission compared to 7% in younger patients. Relapse rates were similar between older and younger patients. Ultimate survival was 25% for older patients and 48% for younger patients. Previous studies with less intensive regimens were associated with a relapse rate of 80% compared to 40% for hyper-CVAD. These data suggest that progress is being made in treating adult ALL but the therapy is associated with an increased rate of non-leukemic deaths in older individuals.

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. These same drugs are also effective in preventing CNS relapses when given in high doses intravenously. Current treatment regimens are associated with only a 2-4% incidence of CNS recurrences. Current efforts are directed at preventing CNS relapses without the use of radiotherapy.

Strategies to Improve Post Remission Therapy for Acute Lymphoblastic Leukemia

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 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 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.[7][8] In addition, Sprycel is more effective than Gleevec for the treatment of Philadelphia chromosome-positive ALL that involves the central nervous system (CNS).[9]

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.[10] 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.[11][12]

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.[13]

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 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.[14] 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.[15] There are already reports of children with ALL responding to single-agent Rituxan or Rituxan in combination with chemotherapy.[16] 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.[17] 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 US 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.[18] 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.[19]

Arranon: Arranon is a drug which has resulted in a 50% response rate in children with refractory T-cell ALL.[20] This drug has now been incorporated into remission induction and consolidation therapy for children with T-cell ALL.[21]

Clolar: Clolar is a new drug that has been primarily evaluated in children with ALL who relapsed after primary therapy.[22] 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.

References:

[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.

[2]Chiaretti S, Li X, Gentleman R, et al. Gene expression profiles of B-lineage adult acute lymphocytic leukemia reveal genetic patterns that identify lineage derivation and distinct mechanisms of transformation. Clinical Cancer Research 2005;11:7209-7219.

[1] Larson RA, Dodge RK, Linker CA, et al. A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 1998;92:1556-1564.

[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.

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

[5] Linker C, Damon L, Ries C, et al. Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. Journal of Clinical Oncology. 2002;20:2464-2471.

[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. Cancer2008;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.

[10] 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.

[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. Cancer2006;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.

[1] Linker C, Damon L, Ries C, et al. Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. Journal of Clinical Oncology. 2002;20:2464-2471.

[2] Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia the greatest benefit is achieved from a matched allogeneic transplant in first complete remission and an autologous transplant is less effective than conventional consolidation/maintenance chemotherapy in all patients: Final results of the International ALL Trial (MRC UKAII/ECOG E2993). Blood 2008;111:1827-1833.

[3] Kiehl MG, Kraut L, Schwerdtfeger R, et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: No difference in related compared to unrelated transplant in first complete remission. Journal of Clinical Oncology 2004;22:2816-2825.

[4] Dombret H, Gabert J, Boiron J-M, et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 trial. Blood. 2002;100:2357-2366.

[5] 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.

[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. Cancer2008;early on-line publication on August 20.

[7] 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.

[8] 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.

[9] 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.

[10] 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.

[11]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.

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

[13]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. Chicago/IL. Abstract # 7006.

[14] 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.

[15] 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.

[16] 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.

[17] 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.

[18] 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.

[19] Larson RA. Three new drugs for acute lymphoblastic leukemia: nelarabine, clofarabine, and forodesine. Seminars in Oncology 2007;34:513-520.

[20] 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.

[21] 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,

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

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