Acute lymphoblastic leukemia (ALL) is a malignant disease caused by the abnormal growth and development of white blood cells (WBC) in the bone marrow and blood. ALL is the most common cancer occurring in children with an annual rate of approximately 30 to 40 new cases per million.
Despite recent advances made in treatment of childhood ALL, numerous important biologic and therapeutic questions still need to be answered in order to achieve the goal of curing every child with ALL. Clinical trials for children and adolescents with ALL are generally designed to compare potentially better therapy with therapy that is currently accepted as standard, or to explore the various biological factors that seem to contribute to better or worse outcomes.
Several studies presented during the 46th Annual Meeting of the American Society of Hematology (ASH) explore these various questions and continue to move science closer to finding a cure for this devastating childhood disease.
"ALL is the most common childhood cancer, representing 23 percent of cancer diagnoses among children," said Richard Larson, M.D., Professor of Medicine and Director of the Hematologic Malignancies Clinical Research Program University of Chicago. "Clinical trials exploring ways to better treat these children are of the utmost importance. Each study brings us one step closer to finding a cure for this devastating childhood illness."
Pharmacogenetics of Minimal Residual Disease Response in Children with Acute Lymphoblastic Leukemia (ALL)
In this study, which was a cooperative effort between several institutions belonging to the Children's Oncology Group, researchers at the Cincinnati Children's Hospital and Medical Center explored whether the presence of minimal residual disease (MRD), the level of leukemia cells present in the blood after remission induction therapy, was related to different variants of genes that normally occur in populations. These inherited genes include polymorphisms, or single nucleotide alterations, at a particular locus or site on a chromosome. Nine specific genes which are known to have different DNA sequences were studied. More than 1,000 children were enrolled across multiple protocols and measured for MRD at day eight and day 28 of remission induction therapy. MRD refers to the quantification of very small numbers of leukemia cells in bone marrow, which are not detectable by microscopic examination.
Results indicate that the presence of MRD at the end of induction, a known adverse risk factor for ALL, is importantly influenced by pharmacogenetic (the interrelation of hereditary constitution and response to drugs) polymorphisms. Results also demonstrate the value of an early endpoint such as MRD versus the more common endpoint of five or 10-year survival rates for determining the variables likely to influence outcome, which aids in the more prompt development of relevant pathophysiologic studies.
More specifically, there was a strong correlation between the presence of MRD and the MTHFR A1298C genotype. The presence of an A allele (genotype A/A or A/C) versus the presence of a C allele only (genotype C/C) corresponded to a higher incidence of MRD (31 percent to 19 percent, respectively). This is significant because methylenetetrahydrofolate reductase (MTHFR) is an enzyme critical to folate metabolism. Folate is necessary for DNA synthesis and repair, and leukemia cells depend on folate for their growth. Therefore, variations in MTHFR could potentially detract from a child's ability to clear residual leukemia following standard treatment.
Similar to MTHFR, the MDR1 2677 G/G genotype had a higher incidence of MRD than the other MDR1 2677 genotypes (39 percent and 25 percent respectively). None of the other pharmacogenetic polymorphisms considered in this trial were associated with the presence of MRD. There was, however, a trend toward an association between VDR (vitamin D receptor) genotype and MRD presence.
"There is a strong need for additional studies to determine the impact of these specific polymorphisms on overall survival," said Stella Davies, MBBS, Ph.D., MRCP, Cincinnati Children's Hospital and Medical Center and lead investigator. "It is our hope that we will someday be able to tailor chemotherapy regimens to each child using his or her genotype, thereby maximizing results and ultimately improving outcomes."
Outcome for Adolescent and Young Adults 16-21 Years of Age (AYA) with Acute Lymphoblastic Leukemia (ALL) Treated on the Children's Cancer Group 1961 Study
Adolescents with acute lymphoblastic leukemia (ALL) represent an understudied subset of the patient population. Adolescents 16 to 21 years of age are eligible for entry onto both children and adult cooperative group trials; however, the rate of participation of adolescents in ALL trials is quite low. Pediatric and adult trials often deliver substantially different therapy. Because adolescents have worse event-free survival rates than younger children with ALL, specific studies aimed at improving outcomes for adolescents are critical for helping this understudied patient population.
Researchers at the University of Chicago Children's Hospital led a clinical trial which included adolescent and young adults to determine the effects of intensification of chemotherapy on treatment outcome. Treatment was stratified based on early marrow response to chemotherapy.
Two hundred and sixty-two young adults ranging from 16-21 years of age were enrolled in the Children's Cancer Group (CCG) 1961 protocol. The study design was based on findings from CCG 1882, which demonstrated that an intensive chemotherapy regimen including high-dose intensity for vincristine, asparaginase and intravenous methotrexate without rescue (augmented BFM) produced a significant improvement in event-free survival and survival for patients with a slow early marrow response (>25 percent blasts in bone marrow on day seven of therapy) compared to a standard BFM therapy. BFM, or Berlin Frankfurt Muenster, refers to the 1976/79 trial of ALL in children which produced impressive disease-free survival rates with a protocol that began with eight weeks of intensive therapy, followed by eight weeks of maintenance therapy, and then another six weeks of intensive treatment (delayed intensification). Augmented BFM included treatment intensification in early treatment phases and added two additional intensified treatment blocks prior to maintenance therapy. For rapid early responders, CCG 1961 attempted to determine whether early treatment intensification, late treatment intensification, or both would improve event-free survival. Patients with slow early response were randomized to the full-augmented treatment arm (increased intensity and increased duration) or the full-augmented treatment arm with additional pulses of idarubicin/cytoxan during the intensification phases of therapy.
The five-year event-free survival rate for adolescent patients in this study was 68 percent; the five-year survival rate was 77 percent. For rapid early responder patients randomized to the augmented intensity arms (both standard and increased duration), the five-year event-free survival rate was 83.2 percent compared with 60.8 percent for patients treated on the standard intensity treatment arms. Within the augmented intensity arms, increased duration made no difference in the event-free survival rate. There was no difference in five-year event-free survival for the two slow early response treatment arms as well (78 percent for augmented therapy with additional pulses of idarubicin/cytoxan versus 74 percent for the augmented only treatment arm).
Five-year event-free survival for patients with <50,000 white blood cells (WBC) at diagnosis was 73.2 percent versus 54 percent for those with >50,000 WBC. A high WBC count is known to negatively impact the response rate. Unlike for younger patients, there was no difference in outcome for males and females for this adolescent-young adult population. These results indicate that early augmented intensity therapy appears to improve outcome for adolescent ALL patients with a rapid early response to induction therapy.
"Cancer that occurs during adolescence poses a special challenge. Although we now have a better understanding for one successful treatment model in this age group, much more needs to be done to better comprehend the reasons behind the lower overall survival rate in adolescents," said James Nachman, M.D., University of Chicago Children's Hospital and lead investigator. "Identifying improved treatments for adolescents with leukemia through increased clinical trial enrollment of this age group should be a top priority."
Outcome of Dana-Farber Cancer Institute (DFCI) Consortium Protocol 95-01 for Children with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)
Although survival outcomes for children with ALL have significantly improved in the past several decades, treatment-related morbidity is still an unfortunate reality with chemotherapy. As cure rates have improved, research has also focused on the recognition and reduction of treatment-related morbidity. One such study, designed to explore new treatment regimens that minimize therapy-related morbidity without compromising efficacy, is a study led by researchers from Dana-Farber Cancer Institute/Children's Hospital Boston.
A total of 491 eligible patients, ranging in age from infancy to 18 years, were enrolled in the study and broken up into two sub-groups, high risk and standard risk patients. High risk patients had at least one of the following criteria: a white blood cell count greater than or equal to 50,000 per micro- liter, age less than or equal to 1 year or greater than or equal to 10 years, leukemia cells present in spinal fluid, the presence of a mass in the chest, T-cell immunophenotype, or a Philadelphia chromosome. All other patients were considered standard risk. Of the patients enrolled in the study, 219 were considered high risk and 272 were classified as standard risk.
This study included three randomized comparisons. First, both standard and high risk patients participated in a randomized comparison of Erwinia- and E. coli-derived L-asparaginase. Secondly, standard risk patients were randomized to receive intrathecal chemotherapy (medicine injected into the spinal fluid to help prevent leukemia from spreading to the central nervous system), with or without cranial radiation (those not receiving cranial radiation received an additional dose of intrathecal chemotherapy), in order to determine whether the substitution of intrathecal chemotherapy for cranial radiation was associated with fewer and less severe late neurocognitive impairments. And finally, high risk patients were randomized to receive doxorubicin (administered during induction and consolidation therapy), with or without dexrazoxane, a drug used to reduce the incidence and severity of heart problems associated with doxorubicin. Median follow-up for patients was 4.6 years.