In the current era, more than 80% of children with acute lymphoblastic leukemia (ALL) are cured with modern intensive chemotherapy regimens. These regimens are based on combinations of drugs that have been around for many years and “are cousins of one another,” Stephen Sallan, MD, Chief of Staff at Dana-Farber Cancer Institute, noted in an interview for this article.
Refinements have been made in homing in on important details, such as which patients require more intensive chemotherapy and who can tolerate the higher risk of side effects, and therapy is now tailored to risk factors, Dr. Sallan explained. But other than that, “there is nothing ‘new-new’ in intensive chemotherapy.”
Studies conducted in the late 1990s are just beginning to be analyzed, and these studies were done with “intensive chemotherapy regimens revved up to the max,” he said.
Several groups have shown that intensive blocks of chemotherapy improve outcome in the range of 80% to 85% in newly diagnosed patients. These groups include the Berlin Frankfurt Munster Group in Europe and the Dana-Farber consortium and the Children's Oncology Group (COG) in the US.
Ability to Measure mMRD
Another important advance has been the ability to measure molecular minimal residual disease (mMRD). However, even when this sensitive measure can identify the presence of mMRD, and thus begin to identify patients who will relapse, there are still no universally effective treatments for relapse, Dr. Sallan said.
Children with potentially curable ALL are being cured, and the intensity of the drugs being used is at its peak, he said.
“We have turned up the volume of chemotherapy to its peak. We have hit a wall. Now we need different drugs and different approaches, and we need to understand the degree of heterogeneity among the 15 to 20 percent of patients who are not cured with chemotherapy.
“The good news is that 80 to 85 percent of children with ALL are cured with modern intensive chemotherapy,” Dr. Sallan continued. But for the 15 to 20 percent of children for whom chemotherapy is not curative, recognizing who these children are and doing something about it remains a formidable challenge.”
Intensive Chemotherapy in Newly Diagnosed Patients
Two studies by COG investigators have changed the way chemotherapy is delivered to newly diagnosed children with ALL, noted Nita Seibel, MD, Professor of Pediatrics at George Washington University School of Medicine and Public Health and Director of Outreach Services in the Division of Hematology/Oncology at Children's National Medical Center in Washington, DC.
Dr. Seibel explained that children and adolescents with a high risk of relapse (i.e., those who are age 10 and over or are over age one with white blood cell counts in excess of 50,000/μl) have not fared as well with standard chemotherapy if they did not show a rapid response by clearing the leukemia blasts from their bone marrow by the seventh day of therapy.
The five-year overall survival rate for this group of children and adolescents used to be no more than about 60%, but in the Children's Cancer Group (CCG) 1882 study, investigators led by James Nachman, MD, found that an augmented chemotherapy regimen—giving more chemotherapy for longer periods of time—could improve the five-year event-free survival rate from 55% to over 75% in 300 responder children and adolescents.
The augmented regimen was given for an additional six months before starting maintenance therapy, and included additional doses of vincristine and asparaginase, and intravenous methotrexate, which was given every 10 days instead of oral medications (6-mercaptocurine and methotrexate) given daily and weekly.
COG investigators then sought to explore what components of the augmented regimen had the biggest impact or were the most effective. The CCG 1961 trial enrolled 2,078 newly diagnosed children and adolescents with high-risk ALL and treated them with standard chemotherapy for 28 days.
Of these children, a total of 1,299 were rapid responders, as determined by bone marrow response on Day 7 of less than 25% blasts.
“We knew from previous studies that this group had an improved outcomes,” Dr. Seibel explained. “The results of the CCG 1961 study were a surprise to us, but were really helpful.
“We assumed that the longer duration of more intensive—or stronger—therapy would be the best arm, but the best outcomes were in the intensive therapy arm without the longer duration of intensive therapy.”
After 28 days of treatment with standard chemotherapy, 1,299 rapid responders were randomized in a 2 x 2 factorial design to standard intensity or increased intensity chemotherapy and then re-randomized to standard duration or increased duration.
“The big news is that we were able to improve five-year event-free survival from 71 to 80 percent with increased [or stronger] intensity [but not increased duration], and we improved overall survival from 84 to 88 percent,” Dr. Seibel said. “That's huge in this disease, because we do so well already that it is hard to show big improvements.”
Further, patients treated with increased (stronger) intensity therapy had very few events (relapse, second malignant neoplasm, death due to other causes) after two years, whereas patients on the standard therapy arm kept having events, she said.
COG oncologists are now using the more intense protocol and building on the success of that to try to improve outcomes further, she added. Other groups use different protocols, such as the group at Dana-Farber and at St. Jude's Children's Hospital.
Outcome After Relapse
Even though improved outcomes are now achieved in newly diagnosed patients with ALL, outcomes are poor following relapse. We still have a long way to go, said Paul S. Gaynon, MD, Director of Clinical Oncology Research at Children's Hospital of Los Angeles and Professor of Pediatrics at the University of Southern California. He estimated that fewer than 40% of patients will survive after a first relapse.
Outcomes are especially poor for children with early marrow relapse—those in a first remission of less than 36 months. With improved primary therapy, event-free survival has increased faster than survival, meaning worse outcomes for the smaller number of patients with relapse, he explained.
“Patients who relapse have come through more morbid therapy with more resistant disease. In the old days, we saw ‘softer’ disease in relapsed patients, but now relapsed patients are harder to cure.”
The choice for relapse has been between chemotherapy and allogeneic hematopoietic stem cell transplant, “but we have lost sight of the shortcomings of both strategies,” Dr. Gaynon said. Transplant outcomes do not include the substantial numbers of patients who fail to achieve remission or maintain in remission long enough to get to transplant or who are judged to be poor transplant candidates because of organ toxicity or infection.
Studies comparing chemotherapy with bone marrow transplant are confounded by selection bias and waiting time bias, he continued. Case control studies show a consistent advantage for hematopoietic stem cell transplant but fail to correct for selection bias. Prospective studies show little or no advantage for hematopoietic stem cell transplant.
“When you track outcomes for all marrow relapse patients, outcomes are poor,” Dr. Gaynon stated. “Too often, we forget that one half of second events in early marrow relapse occur before the median time to transplant. Too often, we lose sight of the fact that any study is a comparison of one chemotherapy approach and one hematopoietic stem cell transplant approach, and results are not generalizable to all chemotherapy and transplant approaches.
“Many are coming to accept that transplant is not the complete answer to the problem of relapse. Our challenge is to improve chemotherapy and transplant outcomes and not compare them endlessly.”
Better understanding of the biology of leukemia may lead to more effective salvage therapies, he said.
Novel drug agents with activity against resistant lymphoblasts are needed. Combinations of monoclonal antibodies with cytotoxic chemotherapy have shown benefit in adult malignancies and analogous combinations with agents like rituximab, alemtuzumab, and epratuzumab may hold promise in the treatment of relapsed ALL.
Understanding the mechanisms of resistance may offer additional clues. Lower disease burden at the time of transplant may prevent relapse after transplant, Dr. Gaynon said.
Transplantation after Relapse
Transplantation is an option for the majority of children in a second complete remission, said Stella Davies, MD, s Director of the Blood and Marrow Transplant Program at Cincinnati Children's Hospital.
For many years, the only option for transplantation was a matched sibling donor. But for the past two decades, matched unrelated donor grafts have been used. “Now, most children, but not all, are able to find a donor,” Dr. Davies explained.
HLA-matched sibling transplants can achieve a better outcome than chemotherapy in patients with early relapse (i.e., less than three years after first complete remission), while outcomes are similar with chemotherapy and bone marrow transplant in patients with a late relapse (i.e., more than three years).
Dr. Davies was senior author of a recent paper (Eapen M et al: Blood 2006 Jun 15;107:4961–4967) showing that the survival rate in patients with early relapse and in second complete remission was 23% with chemotherapy compared with 40% for patients treated with a preparative regimen of chemotherapy and radiation who underwent HLA-matched sibling transplantation.
For children with late relapse, survival was almost identical for chemotherapy and transplantation: 61% with chemotherapy and 60% with transplantation and a preparative regimen of chemotherapy and total body radiation.
The risk of second relapse was higher after non-total-body-irradiation-containing transplant regimens, Dr. Davies noted. The paper was based on a retrospective review of outcomes in 188 patients enrolled on chemotherapy trials and 186 HLA-matched sibling transplants treated between 1991 and 1997.
“It is very important to emphasize that the benefit of transplant comes from total body radiation,” Dr. Davies emphasized. “The common belief is that the adverse effects of radiation outweigh the benefits in children with ALL, but this is not true.”
Improved outcomes in bone marrow transplant can be largely attributed to improved supportive care and better typing and matching methods for unrelated donor grafts, she added.
Gene Arrays & Relapse
William L. Carroll, MD, Professor of Pediatrics at New York University Medical Center, noted that new information from gene array analysis of leukemic cells is paving the way for development of compounds that may improve sensitivity to chemotherapy in children with relapsed ALL. Gene array analysis shows which genes are upregulated and downregulated in cancer.
Dr. Carroll and colleagues conducted a study of matched pairs of gene arrays from patients at initial diagnosis of ALL and at relapse.
“We had samples from the same person at diagnosis and relapse, and we were able to study how leukemia evolves—which genes are ‘turned on’ and which are ‘turned off’,” Dr. Carroll said.
The genes that are activated in relapse tend to be those involved in cell growth and proliferation and DNA repair and those that prevent apoptosis, he explained. In experimental systems, downregulation of those genes rendered cells more sensitive to chemotherapy.
“This is important, because when children relapse, outcome is poor, especially if they are on chemotherapy at the time of relapse,” he said.
Survivin is a particular gene that is upregulated in relapse and makes cells resistant to chemotherapy. Survivin got its name because one of its roles is to prevent apoptosis. Studies of survivin paved the way for the development of agents that block survivin—referred to as anti-sense survivin.
Dr. Carroll and his colleagues are studying the effects of antisense survivin in the laboratory, and if the results are promising, they plan to conduct clinical studies in the future with this compound. The hope is that by decreasing survivin, relapsed ALL cells will become more sensitive to chemotherapy and outcomes will improve.
“This compound has made its way through the pipeline based on knowledge of survivin expression in many cancers, and studies have already been initiated in adults,” he said.
At the same time, Dr. Carroll plans to continue studies of other genes that are upregulated at relapse and develop new compounds that target those genes.
“We don't know yet which genes are critical,” he said. “We do know that cyclin B1, topoisomerase 2A, and other genes are upregulated in relapsed ALL, and we plan to study those genes also because there are compounds that may target them.”
Monoclonal Antibodies in Relapse
Ongoing studies are looking at the use of monoclonal antibodies that target antigens expressed in B-precursor leukemia cells in combination with chemotherapy for children with relapsed ALL.
Elizabeth A. Raetz, MD, Associate Professor of Pediatrics at New York University Medical Center, is lead investigator of a Phase I safety study sponsored by COG and Immunomedics that is looking at the effect of epratuzumab, which targets CD22.
Seventeen children with either initial or late recurrence are enrolled in the ongoing study, with epratuzumab given for two weeks twice weekly for a total of four doses; followed by three courses of chemotherapy. The antibody is given weekly with the first course of chemotherapy. The second and third courses are chemotherapy alone.
The chemotherapy regimen used was defined in a recently completed COG study (COG AALL 01P2).
Also being studied in children with relapsed ALL is alemtuzumab, a humanized monoclonal antibody that targets the CD 52 antigen that is FDA approved for treatment of adults with chronic lymphocytic leukemia (CLL).
There is an ongoing COG study using alemtuzumab for relapsed ALL. This study is led by Anne Angiolillo, MD, at Children's National Hospital in Washington, DC. In the alemtuzumab trial, Dr. Raetz noted, the antibody is being given alone for one course, followed by alemtuzumab with 6-mercaptocurine and methotrexate.
Research on relapse and other phenotypes (i.e., secondary cancers, other late effects that compromise quality of life) provides some clues as to what extent genetic variability contributes to phenotype variability, explained Mary V. Relling, PharmD, Chair of the Pharmaceutical Department at St. Jude Children's Research Hospital.
Clinical studies provide information on genetic variations, including genome wide scans and candidate genes. Variations in candidate genes may be able to predict phenotype, she said, “but this work is still in the discovery phase.”
Laboratory studies complement clinical studies and gene arrays. “We work both ends at the same time: lab studies to clinical studies and back again to lab studies,” she said.
One important area of research is to discover whether there are markers for avascular necrosis, an adverse event of steroid therapy that is being seen with increasing frequency in children with ALL treated with intensive chemotherapy, especially children over the age of 10.
“Although intensified therapy [with steroids] improves outcomes, it can also lead to avascular necrosis,” she said.
Dr. Relling and colleagues at St. Jude have been conducting pharmacogenetic studies of dexamethasone to find markers for risk of avascular necrosis. Thus far, it appears that increased plasma dexamethasone levels and decreased serum cortisol levels may be markers of risk.
“These findings go along with epidemiology, because children over the age of 10 have increased levels of dexamethasone compared with younger children,” she said.
“It is still premature to know how we are going to use these risk factors, but we may be able to use these markers to decide which patients are at very high risk of avascular necrosis and consider using lower doses of dexamethasone in this group.”
Pharmacogenetic studies and lab studies of murine models of ALL will be conducted to see if these studies provide supportive evidence of the clinical studies. “We may find that other drugs given prior to dexamethasone increase the risk of avascular necrosis. Steroids are only one risk factor—risk factors are multifactorial,” she said.
Other work at St. Jude has led to identification of two genetic predictors of relapse: polymorphisms of gluthathione transferase and thymidalate synthase, which are both involved in drug resistance.
Quality of Life
When children are diagnosed with ALL, they are routinely categorized as low or standard risk of recurrence/relapse, or intermediate, high, or very high risk. “Risk stratification is not standardized around the world, but generally at diagnosis, the prospect of cure can be predicted,” said Ronald D. Barr, MB, ChB, Professor of Pediatrics, Pathology, and Medicine at McMaster University in Ontario.
Higher-risk patients are treated with more intensive therapy to reduce the risk, and toxicity is acceptable in that group of patients. However, in low-risk patients, intensive therapy is not needed.
“You don't want to increase the burden of toxicity without improving the odds,” Dr. Barr said. “Quality of life is determined more by the treatment than by the disease. The initial risk stratification and the intensity of the therapy will determine quality of life.”
Quality of life has been studied in childhood ALL in two time frames: the burden of morbidity associated with active treatment and the burden of morbidity due to treatment-related late effects. Much has been written about late effects of treatment in survivors, but less is known about quality of life on active therapy, Dr. Barr explained.
Survivors of childhood ALL have a similar health-related quality of life compared with the overall health in children who have never been treated for cancer, he noted, cautioning, however, that “the overall health of never-treated children is not perfect. Not all children have perfect health, and that includes childhood survivors of ALL.
“It has been a revelation to pediatric oncologists that standard-risk ALL survivors have a quality of life that is indistinguishable from the health of children in the general population.”
Children at higher risk who have undergone cranial radiation have a different quality of life from the general population and from those at standard risk who received less-intensive therapy.
“Nevertheless,” Dr. Barr said, “treatment that cures 90 percent of standard-risk ALL should be considered a home run.”
Morbidity During Treatment
Quality of life during treatment, though, is a different story, Dr. Barr continued. Children with ALL receive two or more years of therapy, and side effects occur. Most side effects are short-lived and don't require hospitalization.
Dr. Barr's group and other investigators have studied the impact of active treatment on health-related quality of life and found that during treatment, health-related quality of life is poor compared with health-related quality of life in the general population. Most of the most bothersome side effects are related to steroids, which make children hyperactive, bad-tempered, and basically difficult to control, Dr. Barr said.
“It would be a bonus if we could minimize side effects without compromising cure rates. Randomized controlled trials of several approaches are being discussed. These include shortening the time of therapy from two years to 18 months and reducing the dose of steroids. It is reasonable to look at lower doses of steroids in children with a high chance of cure.”
Issues in Adolescents & Young Adults
Over the past five years, a series of studies from the US, France, the UK, and the Netherlands, have shown that the age group of adolescents and older children (age 15 to 21), have markedly increased long-term survival when treated by pediatricians on pediatric protocols compared with the same population treated on adult protocols.
In this series, noted Stephen Sallan, MD, Chief of Staff at Dana-Farber Cancer Institute, the five-year survival rate for these young adults treated on pediatric protocols was 64% compared with 38% for those treated on adult protocols.
The same drugs are available to pediatric and adult patients, yet “there is something about either the pediatric culture or the treatment culture” that leads to improved outcomes when young adults are treated according to pediatric protocols, Dr. Sallan said.
“It is difficult and somewhat elusive to quantify why this age group improves on pediatric protocols. It may be the near religiosity with which we treat children, the attention to detail, the urgency, and the push to cure them, as well as the sociology of the disease.”
He explained that ALL is the most common hematologic malignancy in the pediatric population, but ALL is subsumed by the more common cancers such as breast, prostate, lung, and colorectal cancers in the adult population.
Karen Albritton, MD, Director of Adolescent/Young Adult Oncology at Dana-Farber Cancer Institute, said, “People in this group can walk into either door. They are allowed on adult and pediatric protocols. There is no doubt that the data are amazingly replicable in the studies showing that people aged 15 to 21 do markedly better on pediatric protocols.”
Several possibilities for the difference in outcome are being explored, she said. The biology of ALL appears to be similar in this age group. White blood cell counts and chromosomal abnormalities show that the groups studied in these trials are well matched, she said.
The second possibility is that differences in the regimens are responsible for the outcome. Pediatric oncologists tend to use more prednisone, asparaginase, and vincristine, while adult oncologists use less of these drugs and tend to rely on alkylators and more intensive therapy.
Studies that have compared pediatric versus adult protocols in young adolescents and adults find similar remissions at one month, but as time goes on, fewer remissions occur in patients on adult protocols.
Two studies are ongoing to explore the effect of pediatric regimens in ALL. At Dana-Farber, an ongoing single-arm study has enrolled adults aged 18 to 50 on a standard pediatric regimen for ALL.
Cancer and Leukemia Group B and the Southwest Oncology Group plan to study 18-to-30 year olds with ALL treated with the standard COG pediatric regimen for ALL. These studies should provide some insight as to whether the pediatric regimen itself is responsible for improved outcome, Dr. Albritton said.
“We expect to see some improvement when adults are treated on the pediatric protocols, but we don't know what degree of improvement to expect.”
It may turn out that it is not just the regimen, but that giving the regimen in experienced hands with a greater attention to detail is responsible for some of the improvement seen on pediatric protocols, she explained.
Pediatric patients are treated with a higher patient-to-nurse ratio, which could turn out to be important. Also, as Dr. Sallan said, there could be factors operating in the culture of pediatric oncology that lead to improved outcomes compared with adults with ALL.
Participation in Clinical Trials
Adolescents and young adults with ALL and other cancers have suboptimal participation in clinical trials. This age group largely falls through the gap. Dr. Albritton said that about one third of this age group are treated at pediatric hospitals and another one third at academic centers.
“Adolescents and young adults are probably best served at academic centers, and if they were seen there, they probably would have improved participation in clinical trials,” she noted.
Another possible explanation is that people in this age group miss the cut-off age for clinical trials. For example, a 19-year-old is too old for a pediatric trial (the upper age limit is usually 18) and a 17-year old is too young for an adult clinical trial.
Also, there is a misperception, Dr. Albritton said, that adolescents and young adults won't be compliant with the requirements for clinical trial participation, so doctors may be reluctant to enroll them.
Studies that have compared pediatric versus adult protocols in young adolescents and adults find similar remissions at one month, but as time goes on, fewer remissions occur in patients on adult protocols.