Overview

If a complete remission is achieved following remission induction therapy and no further treatment given, over 90% of patients will have a recurrence of leukemia in weeks to months. However, treatment 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.22This 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

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