In this issue

President of medical staff welcomes new fellows and residents

Physician-in-chief congratulates graduates of residency and fellowship programs

Health care's dirty little secret

Texas Children's CME accreditation benefits medical staff and patients

Childhood cancer: The good news!

Texas Children's News for the medical staff

Grand Rounds

Medical staff committees and chairs

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Advisors

Ralph D. Feigin, M.D.
Physician-in-Chief
Texas Children's Hospital
Professor and Chairman
Department of Pediatrics
Baylor College of Medicine

Arnold G. Kagan, M.D.
Clinical Associate Professor of Pediatrics

ZoAnn E. Dreyer, M.D.
Medical Director,
Long-term Survivor Program
Texas Children's Hospital
Associate Professor
Baylor College of Medicine

For members of the Texas Children's Hospital medical staff

Childhood cancer: The good news!

By ZoAnn E. Dreyer, M.D.

Cooperative groups provide the model for success in childhood cancer

Cancer remains the leading cause of non-accidental death in children. Acute lymphoid leukemia (ALL) in children older than one year of age is the most common cancer we see and today one of the most curable. In 1965, only 5 percent of all children with ALL were cured. Today, 70 percent to 80 percent of children with ALL are cured. In fact, the cure rates are as high as 90 percent in some groups of patients whose leukemia has the most favorable prognostic features. How has this incredible progress been possible?

In the late 1950s, pediatric oncologists around the country joined forces to study childhood cancer in an effort to gain a better understanding of the different diseases and conduct clinical trials of various therapies to define the best possible way to treat and cure childhood cancer. This small group of specialists, including Dr. Donald J. Fernbach, founder of Research Hematology later renamed the Texas Children’s Cancer Center, designed the early trials for treatment of a variety of cancers using the few available chemotherapy agents and radiation therapy. These pediatric oncologists led the way in the early development of “cooperative groups” of investigators and institutions that worked together to develop and conduct multi-institutional clinical trials. In an effort to improve support for clinical trials in pediatric cancer in the United States, the Children’s Cancer Group (CCG) and the Pediatric Oncology Group (POG) were formed as the first two major pediatric cooperative groups studying childhood cancer.

Over the years, these clinical trials have allowed us to dramatically improve cure rates – also referred to as event free survival (EFS). By testing what we know (standard therapy) against promising new treatments in a randomized trial using these protocol-based therapies, we are able to ask and quickly answer research-based questions by enrolling large numbers of patients around the country on these protocols. Not only have the efforts of these cooperative group trials been focused on improving disease outcome, but they have also focused on enhancing our understanding of the biology of the disease. We now have a much better understanding of what biologic and clinical features suggest a child will do better or worse and as a result, we are able to design “risk-based” therapy. Risk-based therapy allows us to define the risk of failure or relapse, ensuring that we do not over or under treat anyone.

Moving therapies from the bench to the bedside

Today’s cooperative groups are perfect examples of taking medicine from the bench to the bedside. Many investigators are bench scientists dedicated to gaining a better understanding of cancer cell biology, to the development of new agents and to the exploration of novel therapies, including designing drugs which target specific features of the cancer cell. Working jointly with bench scientists, clinical oncologists are then able to use this new knowledge to design clinic trials for patient enrollment – taking bench science to the bedside.

Progress in infant ALL outcomes as an example of cooperative group success resulting from “bench to the bedside” translational medicine.

The progress in treating infants with ALL under the age of one year serves as a perfect example of the success one can attribute to studying diseases in a cooperative, or collaborative, group setting. ALL in infancy differs significantly from ALL in older children not only in presentation but also in prognostic factors, response to therapy and outcome. Although infant ALL represents only 4 percent of childhood ALL with an annual incidence of 20 per one million infants at risk, the outcome for this small group of patients has been dismal with published EFS rates range from 17 percent to 43 percent ^(1-5) .

In the early 1980s, most infants were treated on the high risk, more intensive arms of pediatric ALL protocols designed for children greater than one year old at diagnosis. Outcomes were poor characterized by short-term disease control, early relapse and 5 year EFS in the range of 20 percent ^(6-8). Subsequently, many groups have developed intensified, infant specific therapy with some improvement increasing average EFS to 30 percent to 45 percent ^{(1, 9-13)}. Despite good success in achieving remission, nearly two-thirds of infants continue to relapse within six to 12 months following their initial diagnosis ^{(1,7, 9)}.

Historically, risk factors associated with a poorer prognosis in infant ALL appear interrelated and include evidence of high-risk 11q23 translocations in the chromosomal makeup of the leukemia blasts. These translocations are usually associated with a rearrangement in the MLL gene located in the region of the 11q23 translocation. ^{(1, 11, 13, 14-18)}. The MLL gene rearrangement occurs in approximately 70 percent to 80 percent of infants with ALL and is associated with a very poor EFS of only 20 percent to 30 percent. Infants whose blasts do not have evidence of the MLL gene rearrangement have had better outcomes with EFS ranging from 40 percent to 60 percent. Infants with ALL also present with much higher WBC counts than older children. Presenting white counts greater than 50,000 x 109/1 and age < six months at diagnosis have also been considered to be poor prognostic features with the poorest outcome with EFS ranging from 10 percent to 30 percent ^{(1, 8-10, 19)}.

In an effort to address early relapse and poor EFS in infants with ALL, the Pediatric Oncology Group (POG) designed a novel trial (POG 9407) using shortened, highly intensified therapy. To address early relapse, early induction intensification began after just three weeks of induction rather then the usual four weeks of less intensive induction. To further intensify therapy, all drugs with the exception of vincristine and intrathecal therapy were dosed using body surface area rather than using traditional infant dose reductions based on weight and age. With this increased intensity of therapy, the overall duration of treatment was shortened to 46 weeks rather than the more typical 104-plus weeks. Prior to this clinical trial opening in all POG institutions, it was piloted here at Texas Children’s Cancer Center and proved to be quite promising ⁽²⁰⁾. Based on this early pilot study data and acting as Principal Investigator (PI), the trial opened throughout all POG centers in 1996.

POG 9407 ran in parallel with a Children’s Cancer Group (CCG) trial directed by Dr. Patricia Dinndorf (CCG1953) as PI. These trials were identical for the first 10 weeks of therapy then diverged considerably. Although the CCG study continued to use intensified therapy, it also included a much longer maintenance phase of therapy resulting in a total duration of therapy lasting 104 weeks compared with 46 weeks of treatment on the POG study. To further address the historically poor outcome for infants with ALL, stem cell transplant (SCT) was offered for those infants with the very high-risk MLL gene rearrangement and the poorest projected outcomes. Following completion of the first 10 weeks of identical therapy, infants with the MLL gene rearrangement and appropriate donors were eligible were to receive SCT. In the CCG study, such infants were mandated to SCT while in the POG study, SCT was elective. The results of SCT portion of these trials were analyzed jointly.

Between 1996-2001, 71 infants were registered nationally on the POG study. Of those, 17/71 were < 90 days of age at diagnosis and thus considered extremely high risk. The median white cell count at presentation was 93,000 x 109/1 for all patients and 195,000 x 109/1 for those < 90 days of age. Two thirds of the infants had the high risk MLL gene rearrangement in their leukemic blast cells.

Infants on this novel POG study demonstrated a marked improvement in event free survival (EFS) particularly for infants > 90 days of age at diagnosis. In that group, the EFS at 5 years was nearly 53 percent – superior to the EFS of 20 percent to 30 percent reported in previously published trials. However, the EFS remained dismal for those < 90 days of age. Remarkably, the prognostic factors historically deemed most significant, the MLL gene rearrangement and presenting white cell count (</> 300,000 x 109/1), were not as important in predicting outcome in this trial as age at diagnosis (</> 90 days) ⁽²¹⁾.

An analysis of the combined SCT outcomes on the CCG and POG trials held further surprises. In a combined infant population of 132 patients with the MLL gene rearrangement, 53 had SCT. Of the remaining infant population, 47 infants served as the control population. This group was comprised of infant with the MLL gene rearrangement who did not undergo SCT and survived in remission 143 days or the median time to SCT. When comparing the EFS between patients who did have SCT with those who received intensive chemotherapy alone, there was not a statistically significant difference in outcome, thus SCT offered no advantage over intensive chemotherapy alone. This study represents the largest prospectively studied population of infants with ALL transplanted in first remission. As a result of this trial, we are able to conclude that SCT is no longer indicated in first remission ⁽²²⁾.

In 2001, CCG and POG merged into one group, now known as the Children’s Oncology Group or COG. COG represents one of the largest collaborative groups of investigators dedicated to the study of childhood cancer in the world. Following this merger and remaining as PI, POG 9407 was modified slightly and adopted as the national trial for infants with ALL . In total, 142 infants were registered on this successor study (COG 9407). The study completed accrual approximately one year ago.

The outcomes of CCG-1953, POG 9407 and COG 9407 have allowed us to identify the prognostic features of greatest importance for infants treated on this therapy. Age < 90 days at diagnosis and leukemic blasts with the MLL gene rearrangement remain the most critical factors. The improved outcomes observed with these trials allow us to design the next infant ALL trial building on this new knowledge. We are now able to conclude that shortened therapy is as successful as longer therapy lasting in excess of 104 weeks. In light of the improved EFS in infants greater than three months of age including those with blasts with the MLL rearrangement, we were able to demonstrate that SCT in first remission does not offer an advantage over shortened, intensified chemotherapy. Thus, we can now avoid exposing infants to the much greater immediate and long-term untoward side effects, which can result from SCT.

As in older children with ALL, the ability to complete randomized trials in a reasonable period of time with adequate statistical power is key. With the results of the infant trials described above, our successor study will use risk based therapy testing COG 9407 (now considered standard therapy) against the identical therapy with the addition of a novel agent directed at a particular enzymatic activity felt to be critical to sustaining leukemic blast activity. This will be the first randomized trial in infant ALL. Thus, as we have learned through the years, multi-institutional cooperative group trials testing novel therapeutic approaches hold the key to success for children with cancer.

ZoAnn E. Dreyer, M.D., is medical director of Long-term Survivor Program at Texas Children’s and associate professor at Baylor College of Medicine.

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