Relapsed Childhood Acute Lymphoblastic Leukemia
Childhood Acute Lymphoblastic Leukemia: Refractory
Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/2018)
Children with progressive or relapsed 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 leukemia 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. Patients with the longest duration of first remission tend to have the best outcomes. Thus, patients are categorized into those with early and late relapses, with the best survival in patients who relapse beyond two years from diagnosis.
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 many patients, an allogeneic stem cell transplant from a related family member, an unrelated donor or from umbilical cord blood offers a possibility for control or cure of the leukemia. For more information go to Allogeneic Stem Cell Transplant. Other patients may choose to participate in clinical trials evaluating new treatments.
Treatment of Patients Failing Induction
Children with ALL who do not 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. Currently, the best treatment for patients failing induction treatment is an allogeneic stem cell transplant.
Only 5% or less of children with ALL will fail remission induction. Reinduction therapy with the addition of chemotherapy agents not used in the initial induction is usually attempted. Patients who respond to second-line induction therapy are usually offered an allogeneic stem cell transplant from a related or unrelated donor or from umbilical cord blood. Since such a small number of patients have primary refractory ALL there are no recent articles in the literature that deal specifically with this subject. However, the goal of reinduction therapy is to prepare the patient for an allogeneic stem cell transplant from a related, unrelated donor or from umbilical cord blood which offers some prospect of long-term disease control. Go to Allogeneic Stem Cell Transplant for more information.
Treatment of Patients Relapsing after an Initial Remission
Children who have ALL that relapses after an initial complete remission can be cured with standard chemotherapy, autologous stem cell transplant or allogeneic stem cell transplant. Patients who experience an isolated leukemia recurrence in the testicles can be cured two-thirds of the time with additional chemotherapy and radiation to the testes. Unfortunately, the majority of patients relapse in the bone marrow and/or central nervous system where cure is more difficult.
Researchers affiliated with the Children’s Cancer Study Group have reported an 81% second remission rate for children with ALL in first marrow relapse. This study evaluated a strategy of three blocks of multi-agent chemotherapy in 124 children with ALL in first marrow relapse. Following completion of the first block of therapy the complete remission rate was 81%. The other 2 blocks of therapy were for consolidation of the second remission. For children who had a relapse 36 months are more after diagnosis the second complete remission rate was 96% suggesting that this group could potentially be cured. Children who relapsed in less than 36 months and especially those relapsing within 18 months of diagnosis had a significantly lower second complete remission rate. These researchers also found that outcomes were better in children who had no detectable disease at the end of treatment.
Treatment Following Successful Second Remission
Children with ALL who achieve a second remission can be cured with consolidation and maintenance therapies similar to that administered during first remission if they have good risk features. The most important feature is the time from diagnosis to first relapse. Patients who relapse two years or more from diagnosis have a good prospect of being cured with further chemotherapy. Patients who relapse early and/or have intrinsically poor risk features are rarely cured by chemotherapy and are usually offered an allogeneic stem cell transplant.
Some studies have suggested that patients who have an early relapse have a better survival following an allogeneic stem cell transplant compared to continued intensive chemotherapy but not all studies have confirmed this observation. A recent study by the Children’s Cancer Study group showed a 30% survival for of children with ALL who had a relapse within 12 months of diagnosis and were treated with allogeneic stem cell transplantation, autologous stem cell transplantation or continued intensive chemotherapy. 
Results from a 2002 analysis by the International Bone Marrow Transplant Registry (IBMTR) reported that allogeneic stem cell transplants from unrelated donors produce similar results to related transplants in children with ALL in second remission. In this study the 5 year survival was 22%. However, a more recent analysis of IBMTR data shows a 62% survival for children with ALL in second remission and 33% survival for those transplanted with more advanced disease suggesting significant progress between the two reports. This study also showed that results of unrelated donor transplants were better when bone marrow was used as a source of stem cells rather than peripheral blood stem cells, which is more commonly used in adults.
Clolar® (clofarabine): Clolar is a new drug that has been approved by the US Food and Drug Administration for the treatment of children who have failed two or more treatment regimens. In a European multi-center trial children with ALL who had received two or more prior treatment regimens has a 26% response rate.
Treatment of Subsets of Childhood-ALL
Philadelphia Chromosome Positive ALL: Gleevec® (imatinib) is a tyrosine kinase inhibitor that has now been incorporated into remission induction, intensification and maintenance treatments of childhood Philadelphia chromosome-positive ALL. The impact of this strategy on treating relapsed patients again with Gleevec is unknown. Gleevec is active in children who relapse following remission induction or after failure of allogeneic stem cell transplantation. Previous studies have suggested that the appropriate strategy in relapsed patients with Philadelphia chromosome-positive ALL is to administer Gleevec with other chemotherapy agents to reduce the leukemia burden and proceed as soon as possible to an allogeneic stem cell transplant. There is much more experience with Gleevec in refractory ALL in adults. For more information on this topic go to Adult Acute Lymphoblastic Leukemia.
Isolated Brain Relapse: With modern intrathecal treatment, only 5-10% of children with ALL will experience a leukemia recurrence in the brain. Unfortunately, patients with recurrent leukemia in the brain usually have a poor outcome because the leukemia ultimately recurs in the bone marrow and blood as well. In the past, treatment for a child with a brain recurrence consisted of administering chemotherapy into the spinal fluid followed by radiation therapy to the spine and head. Unfortunately this approach was associated with major late complications. Recent studies have focused on less toxic means of treating central nervous system (CNS) relapses. For example, researchers affiliated with the Childrens Oncology Group reported the outcomes of 76 children with an isolated CNS relapse using prolonged systemic chemotherapy that penetrates the brain, chemotherapy administered intrathecally and reduced doses of cranial radiation and no radiation to the spine. Patients in this study were stratified into those who relapsed within 18 months of diagnosis who received more radiation therapy to the brain and those who relapsed after 18 months who received less radiation to the brain. All receive 12 months of systemic and intrathecal chemotherapy. Patients who relapsed within 18 from diagnosis had a 51% 4-year event-free survival compared to 78% for those with late CNS relapses.
Testicular Relapse: Patients who have an isolated relapse in the testes are treated with chemotherapy plus radiation therapy. The results of treatment of isolated testicular relapse depend on the timing of the relapse. The 3-year event-free survival of boys with overt testicular relapse during therapy is approximately 40%; it is approximately 85% for boys with late testicular relapse.
Strategies to Improve Treatment
While significant progress has been made in the treatment of leukemia, better treatment strategies are still needed. Future progress in the treatment of leukemia will result from continued participation in appropriate clinical studies. Currently, there are several areas of active exploration aimed at improving the treatment of relapsed or refractory ALL in children.
Stem Cell Transplant: High-dose chemotherapy and autologous or allogeneic stem cell transplant are currently superior treatment options for many patients with relapsed or refractory ALL. To learn about new developments with these therapies, go to Allogeneic Stem Cell Transplant or Autologous Stem Cell Transplant.
New Drugs or Regimens: All new drugs for the treatment of patients with ALL are tested first in patients with relapsed or refractory disease. Development of new multi-drug treatment regimens that incorporate new or additional anti-cancer therapies for use as treatment is an active area of clinical research.
New Tyrosine Kinase Inhibitors:
Sprycel® (dasatinib): Sprycel is a newly developed tyrosine kinase inhibitor that is more than 300 times more active than Gleevec for inhibition of Bcr-Abl (the abnormal protein produced by the Philadelphia chromosome). Sprycel is active in patients with Philadelphia chromosome-positive chronic myeloid leukemia that is resistant or intolerant to Gleevec, and can also produce complete cytogenetic remissions in patients with ALL who have failed Gleevec. In addition, Sprycel has been used to successfully treat patients with Philadelphia chromosome-positive leukemia that involves the central nervous system (CNS). One of the problems with Gleevec is that it does not penetrate the blood-brain barrier. Researchers involved in the current study stated that preclinical studies have shown that Sprycel is more effective than Gleevec for treatment of Philadelphia chromosome-positive leukemia that involves the CNS. They also report significant drug activity in 11 patients with Philadelphia chromosome-positive leukemia in the CNS. All patients responded, and seven of 11 had complete, long-lasting responses.
Tasigna® (nilotinib): Tasigna is an agent that inhibits the tyrosine kinase activity of the BRC-ABL oncogene in Philadelphia chromosome-positive leukemias. Tasigna is reported to have greater efficacy than Gleevec in Philadelphia-chromosome positive CML. Tasigna has reported activity in patients with refractory ALL but is still in Phase II testing and has yet to be studied in children.
Monoclonal antibodies are proteins that can be made in the laboratory and are designed to recognize and bind to very specific sites on a cell. This binding action promotes anti-cancer benefits by eliminating the stimulating effects of growth factors and by stimulating the immune system to attack and kill the cancer cells to which the monoclonal antibody is bound. This approach delivers additional treatment specifically to cancer cells and avoids harming the normal cells. Some monoclonal antibodies can locate cancer cells and kill them directly. However, some antibodies have to be linked to a radioactive isotope or a toxin in order to kill cells and the antibodies essentially serve as a delivery system. Monoclonal antibodies can be administered alone or with chemotherapy and are being evaluated to determine whether they can improve cure rates.
Monoclonal antibodies directed at tumor antigens have made a major impact in the treatment of cancer over the past two decades. The major advantage of monoclonal antibody therapy is that the toxicities are not the same as for chemotherapy and when added to chemotherapy there is little increase in toxicity. However, there has been little progress in the development of monoclonal antibodies useful for the treatment of childhood ALL. However, this situation may be changing. Researchers from New York University have reported that epratuzumab, a humanized monoclonal antibody that targets CD22 antigen, is effective alone or in combination for the treatment of ALL. This study showed that epratuzumab could be safely added to chemotherapy with improved responses in patients with advanced ALL. A logical step would be to add epratuzumab to induction therapy.
There is emerging evidence that the anti-CD20 antibody Rituxan® (rituximab) has activity in some patients with ALL. A recent study has suggested that CD20 is upregulated in many cases of childhood ALL, making this disease a target for Rituxan. 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 CD 20 positive. This is expected to be an area of intense research in the near future.
Arranon® (nelarabine, 506U78): 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. Arranon was approved by the US Food and Drug Administration (FDA) in 2005 for the treatment of T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in patients who have progressed following at least two prior standard treatment regimens. Results prompting approval included data demonstrating responses or remission in 21% of adults and 23% of children.
Talotrexin: Talotrexin is currently in a multicenter phase I/II trial being evaluated in the treatment of relapsed or refractory ALL. Talotrexin ultimately inhibits DNA synthesis in tumor cells and is being developed for the treatment of various types of tumors. This drug was granted orphan status for the treatment of ALL in 2006. This agent is a possible replacement for methotrexate.
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.
 Raetz EA, Borowitz MJ, Meenakshi D, Reinduction platform for children with first marrow relapse of acute lymphoblastic leukemia. Journal of Clinical Oncology 2008;26:3971-3978.
 Gaynon PS, Harris RE, Altman AJ. Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children’s Oncology Group study CCG-1941. Journal of Clinical Oncology 2006;24:3150-3156.
 Bunin N, Carston M, Wall D, et al. Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission. Blood.2002; 99: 3151-3157.
 MacMillan ML, Davies SM, Nelson GO, et al. Twenty years of unrelated donor bone marrow transplantation for pediatric acute leukemia facilitated by the National Marrow Donor Program. Biology of Blood and Marrow Transplantation 14:16-22.
 Kearns P, Michel G, Neiken B, et al. BIOV-111 a European phase II trial of aClorarabine (Evoltra® in refractory and relapsed childhood acute lymphoblastic leukemia. Blood 2006;108: abstract number 1864.
 Kirk R, Schultz W, Bowman P, et al. Improved early event-free survival (EFS) in children with Philadelphia chromosome-positive (PH+) acute lymphoblastic leukemia (ALL) with intensive imatinib in combination with high dose chemotherapy: Children’s Oncology Group (GOG) Study:AALL0031. American Society of Hematology 2007. Blood 2007;110:abstract number 4.
 Kolb EA, Pan Q, Ladariyi M. Imatinib mesylate in Philadelphia chromosome positive leukemia in children. Cancer 2003;98:2643-2650.
 Barredo JC, Devides M, Lauer SJ, et al. Isolated CNS relapse of acute lymphoblastic leukemia treated with intensive systemic chemotherapy and delayed CNS radiation: a pediatric oncology group study. Journal of Clinical Oncology 2006;34:3142-3149.
 Wollford MM, Smith SD, Shuster JJ, et al. Treatment of occult or late overt testicular relapse in children with acute lymphoblastic leukemia. Journal of Clinical Oncology 1992;10:624-630.
 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.
 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.
 Piccaluga PP, Paolini S, Marinelli G, et al. Tyrosine kinase inhibitors for Philadelphia chromosome positive adult acute lymphoblastic leukemia. Cancer 2007;110:1178-1186.
 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.
 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 immumotherapy. Blood 2008;Epub on September 9.
 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.
 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.
 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.
 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.