Relapsed or Refractory Adult Acute Lymphoblastic Leukemia
Relapsed or Refractory Adult ALL
Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/2018)
Patients with progressive or relapsed adult ALL remain curable despite failing initial treatment. Patients failing treatment can be divided into two broad categories. Patients who fail to achieve an initial complete disappearance or remission of their cancer following a complete course of remission induction chemotherapy treatment are referred to as “induction failures”. Patients who achieve a complete remission to initial treatment and then experience a cancer recurrence are said to have relapsed leukemia. Relapse of leukemia may occur several months to years after the initial remission; however the majority of relapses occur within two years of initial treatment. Refractory is a term that implies that patients have failed at least one treatment regimen after a relapse.
Patients who fail induction treatment or relapse have essentially two choices of therapy. Additional treatment with chemotherapy is rarely curative and some patients will choose a palliative approach where drugs are administered in non-toxic doses to keep the disease under control for as long as possible. In this situation, the emphasis is on the quality of life and supportive care measures.
The alternative approach is to receive more intensive treatment or participate in clinical studies in an attempt to produce a complete remission. For some patients, an allogeneic stem cell transplant offers a possibility for control or cure of adult ALL. Other patients may choose to participate in clinical trials evaluating new treatments.
An allogeneic stem cell transplant is a procedure that is performed to repair the damage caused by high-dose chemotherapy. High-dose chemotherapy (HDC) kills more cancer cells than lower-dose conventional chemotherapy. Unfortunately, HDC also kills more normal cells, especially the blood-producing stem cells in the bone marrow. Stem cells are immature cells produced in the bone marrow that eventually develop into red blood cells, which provide oxygen to tissues; white blood cells, which fight infection; or platelets, which aid in blood clotting. The treatment strategy utilizing stem cell transplant is an attempt to restore the blood-producing stem cells after HDC has reduced them to dangerously low levels. When stem cells reach critically low levels from HDC, complications such as anemia, infection and bleeding can occur. Thus, it is imperative to restore stem cell levels as quickly as possible. An allogeneic stem cell transplant utilizes stem cells collected from a related or unrelated donor or from umbilical cord blood. For more information go to: Allogeneic Stem Cell Transplant.
The information provided here describes some of the commonly used strategies and some of the investigative studies being carried out to improve treatment of patients with ALL who fail conventional therapies.
Treatment of Patients Failing Induction
Patients who are unable to achieve a complete remission with initial standard chemotherapy are rarely curable with additional standard chemotherapy treatments. In addition, high-dose chemotherapy and autologous stem cell transplant is rarely a treatment option because the bone marrow contains many leukemia cells. Since the current complete remission rate is over 90% in adults with ALL, few patients will fall into this category. Currently, the best treatment for patients failing induction treatment is an allogeneic stem cell transplant. A transplant can be performed in first relapse or after an attempt to produce a remission with a chemotherapy regimen different than that used for induction. Patients with adult ALL who receive a related or unrelated donor stem cell transplant in other than first complete remission have a long-term disease-free survival of 27%. The best survivals are seen in those patients who achieve a remission with reinduction chemotherapy and the worst survivals are in those who were refractory to attempts to produce a remission.
Reinduction chemotherapy with standard chemotherapy drugs has been effective in producing complete remissions in some patients, but there are no cures without an allogeneic stem cell transplant.
Treatment of Patients Relapsing after an Initial Remission
Patients with adult ALL that relapses after an initial complete remission can be cured with standard chemotherapy, autologous stem cell transplant, or allogeneic stem cell transplant.
The timing of relapse in relation to initial diagnosis and treatment is important. Patients who relapse while receiving, or shortly after receiving, chemotherapy are unlikely to be cured with further chemotherapy. However, if the relapse occurs many months or years after discontinuing maintenance chemotherapy, many can achieve a second remission with re-institution of chemotherapy similar to that used in initial treatment. However, few of these patients are cured without a stem cell transplant.
Standard-dose chemotherapy can induce a complete remission in 10%-30% of adults, but few patients are cured. The average duration of survival is 5-6 months and less than 5% of adult patients survive 5 years after relapse.
Regimens Used for Reinduction Treatment
A number of regimens have been evaluated for the treatment of patients with relapsed ALL. A few of the more common regimens will be listed below:
High-Dose Idamycin® (idarubicin) and Cytosar® (cytarabine):Various doses and schedules of Idamycin and Cytosar have been used to treat relapsed adult ALL over the past two decades. One of the more recent studies reported a complete remission rate of 44% with a median disease-free survival of 6 months.
Cytosar, Amsidine® (amsacrine) and VePesid® (etoposide): Researchers from France have reported a complete remission rate of 40% with the combination of Cytosar, Amsidine and VePesid in patients with relapsed ALL, with a disease-free survival of 12% at three years. All long-term survivors had received an allogeneic stem cell transplant after remission induction.
Drugs Recently Approved by the US Food and Drug Administration
Two new drugs that are analogs of the commonly used chemotherapy drug 6-mercaptopurine have been approved by the FDA for treatment of refractory patients with ALL: Clolar® (clofarabine) and Arranon® (nelarabine, 506U78).
Arranon: Arranon is a drug which has resulted in a 50% response rate in children with refractory T-cell ALL. This drug has now been incorporated into remission induction and consolidation therapy for children with T-cell ALL.
Clolar: Clolar is a new drug that has been primarily evaluated in children with ALL who relapsed after primary therapy.
Allogeneic Stem Cell Transplantation
Allogeneic stem cell transplantation from a related or unrelated donor or by using umbilical cord blood offers the best chance of long-term disease-free survival in patients with relapsed ALL. A large study recently reported that patients with adult ALL who receive a related or unrelated donor stem cell transplant in other than first complete remission have a long-term disease-free survival of 27% (see reference 1).
Treatment of Philadelphia Chromosome-Positive ALL
Most current patients with ALL in relapse will have failed Gleevec® (imatinib). However, for patients not receiving up-front Gleevec this drug can be used in salvage regimens. Researchers from France have reported that high-dose Gleevec combined with vincristine and dexamethasone produced complete remissions in 90% of patients with Philadelphia chromosome-positive ALL in relapse.
Some patients with Philadelphia chromosome-positive ALL become refractory to Gleevec due to the development of mutated leukemic clones. However, there are now two drugs currently approved by the US Food and Drug Administration (FDA) for treating adult ALL patients that are refractory to 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 are refractory to Gleevec. In addition, Sprycel is more effective than Gleevec for the treatment of Philadelphia chromosome-positive ALL that involves the central nervous system (CNS). This is because Gleevec does not get into the central nervous system while Sprycel does.
Tasigna® (nilotinib): Tasigna is another tyrosine kinase inhibitor which has more potency than Gleevec. Tasigna produces significant remissions in patients with adult ALL who are refractory to Gleevec.,
Strategies to Improve Treatment of Relapsed or Refractory Adult ALL
The development of intensive multi-agent chemotherapy induction regimens, advances in stem cell transplantation, improvements in supportive care, and patient and physician participation in clinical studies have resulted in steady progress in the treatment of adult ALL. The following strategies are currently being evaluated alone or in combination for the purpose of further improving treatment.
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. Increasing dose intensity may improve treatment outcomes, but is also associated with increased side effects; 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.
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).
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. 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. 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. There are already reports of children with ALL responding to single-agent Rituxan or Rituxan in combination with chemotherapy. 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. 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. Experience with treating adult patients with CD33 positive ALL is limited.
Strategies to improve treatment of patients who fail remission induction are also discussed in the section on Allogeneic Stem Cell Transplant.