As part of its series recognizing Childhood Cancer Awareness Month, SMA spoke with Frederick Goldman, MD, Professor of Pediatrics at the University of Alabama at Birmingham, and Director of the Lowder Pediatric Blood and Marrow Transplantation Program at Children’s of Alabama.
The Lowder Pediatric Blood and Marrow Transplantation (BMT) Program at Children’s of Alabama has been in place since 2000, and more than 300 patients have been transplanted during that time. Approximately 20-30 patients are transplanted per year with most receiving an allogeneic bone marrow transplant. In allogeneic transplants, donors are from someone other than the patient, either from a related or unrelated person. This contrasts with an autologous stem cell transplant, where the patient is their own donor, and hematopoietic stem cells are first harvested from the patient prior to them receiving them at a later time. In both types of transplants, patients first receive a preparative regimen, which usually entails high doses of chemotherapy, followed by the infusion of hematopoietic stem cells. Although most people may recognize the term “bone marrow transplant” or BMT, Dr. Goldman explained it is now referred to as a hematopoietic stem cell transplant. The reason for this is that while in the past, the source of hematopoietic stem cells was always from bone marrow, we now have the ability to collect and isolate these same hematopoietic cells from other sources, including the peripheral blood or umbilical cord blood.
The BMT program offers transplants for a wide range of diseases, both malignant and non-malignant conditions. Dr. Goldman specializes in transplanting patients with non-malignant conditions, including immune deficiencies and bone marrow failure syndromes such as Diamond-Blackfan anemia, Dyskeratosis congenita, Fanconi anemia, and Schwachman-Diamond syndrome. In marrow failure disorders and immune deficiencies, allogeneic transplants are most often performed using reduced-intensity preparative regimens. These “preps” utilize less intense chemotherapy and are generally more easily tolerated. In contrast, fully ablative transplants, which are often necessary in malignant conditions such as acute leukemia, may be more important to help eradicate any remaining malignant cells. Dr. Goldman added “We are coming to realize we don’t have to give all patients the same transplant preparative regimen, and the type of prep used is best based upon the disease, donor source, and other clinical measures of organ function”.
Leukemia, either acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) is the most common disease for which a transplant is done at Children’s of Alabama. For some “high risk” leukemia patients, transplant is recommended early after initial diagnosis based upon certain molecular and genetic tests that predict disease relapse. In other instances, transplant may only be recommended if a patient with leukemia relapses while undergoing conventional chemotherapy treatments. Even with transplant there is always the potential for patients to relapse with their original leukemia. Using very sensitive tests we are now able to evaluate for “minimal residual disease” in the marrow, and were this to be found, new cell therapy strategies are being employed at Children’s of Alabama to keep these patients in remission.
“When a patient undergoes a hematopoietic stem cell transplant, the infusion, or “transplant” of the stem cells is actually the easy part. The much more challenging aspect of transplant relates to managing the myriad of complications that can occur after the transplant. Such complications may be direct toxicities of the chemotherapy, infections, severe kidney, liver, or lung dysfunction, or the development of graft versus host disease. In transplant we often employ a prophylactic strategy, as it is far easier to prevent a complication than it is to treat it”.
Finding a donor for Allogeneic Transplants
In an allogeneic transplant, the ideal donor is most often a brother or sister who is HLA identical (10/10 match). However, the likelihood of a full sibling being perfectly matched is only 25%, and with smaller families these days, this can be a problem. When a family member is not available, a donor search is undertaken through the National Marrow Donor Program (NMDP). The NMDP is a registry that has nearly 10 million potential donors enrolled, and quite often we are able to identify a matched unrelated adult who is able to donate bone marrow. Of note, if anyone is interested in being placed on the registry, one can simply complete paperwork and undergo a cheek swab at your local Red Cross. Unfortunately, there is an underrepresentation of ethnic or minority donors in the registry, and locating a 10/10 matched unrelated adult donor may not be possible. In such instances we often resort to using a cord blood donor, as for these sorts of transplants, full matching is not required. It is very rare that we are unable to locate a cord blood donor that is adequately matched. However, the limitation of cord blood relates to the size of the cord blood unit and how many cells are in it. For large pediatric patients or adults, finding a cord blood unit with sufficient cell numbers can be difficult. Not surprisingly, there is also a shortage of minority donors in the cord blood registries. Plans are currently in place to expand the collection of potential cord blood donors in the state of Alabama.
Autologous transplantation is currently the treatment of choice for certain conditions, including relapsed Hodgkins and Non-Hodgkin lymphoma, neuroblastoma, and certain types of brain tumors. Approximately one-third of all stem cell transplants done at Children’s of Alabama are autologous. In some instances patients may receive multiple autologous transplants, or tandem transplants, as a way to keep the cancer under control. Autologous transplants are similar to allogeneic transplants in that both receive high dose ablative chemotherapy prior to the infusion of stem cells. Many complications are also similar, including the potential to harm organs and a predisposition to infection. However, there is no graft versus host disease in autologous transplantation, as a patient gets their own immune cells back. In general, recovery is quicker and long term complications are less frequent with autologous transplants. According to Dr. Goldman, once a patient is approximately a month past their transplant date, they are often referred back to their primary hematology/oncology physicians. Dr. Goldman states “We are currently participating in several national studies through the Children’s Oncology Group (COG) where autologous transplantation is used for high risk neuroblastoma and ATRT, a rare brain tumor. Results are encouraging, and many patients are long term survivors and living free of disabilities. Nonetheless, more work needs to be done to obtain higher cure rates for these conditions“.
What is Graft versus host Disease?
Graft versus host disease, or GVHD, is an immune complication found after an allogeneic transplant and is related to the fact that donor immune cells that are present in the graft recognize the patient tissue (host) as being foreign. Acute GVHD can attack the skin, GI tract, and liver, and usually occurs within the first three months. Chronic GVHD usually occurs later and can affect nearly every organ of the body. In some instances, low grade GVHD can be advantageous as it has a concomitant graft versus leukemia effect, effectively preventing disease relapse. However, in non-malignant conditions there is no advantage in developing any GVHD. Also, advanced grades of GVHD are associated with lower survival rates and higher incidence of severe infections. Dr. Goldman states “It is always a fine line between not enough and too much GVHD, and much attention is paid to closely monitoring a patients clinical condition and their levels of immunosuppressive medications. He also noted that while GVHD immunosuppressive therapies are becoming better and safer, they are not perfect and trying to predict who develops GVHD and determining the best drugs to use can be difficult. To this end, Dr. Goldman is working with Joseph Chewning, MD, an Associate Professor of Pediatrics who also sees transplant patients at Children’s. Dr. Chewning has a basic research laboratory that uses a mouse model to study the cause and effects of GVHD.
Sickle Cell Disease
Another focus area of the program is transplanting patients with sickle cell disease. The pediatric hematology service at Children’s of Alabama currently cares for more than 1000 patients with this condition. As Dr. Goldman explained, while transplant is the only known cure for this condition, it is still not yet known which sickle cell patients would benefit the most from this procedure. Many hematologists and transplant physicians believe that sickle cell patients with matched sibling donors should be transplanted early in the course of their disease, prior to the development of complications of their underlying disease. For patients without a sibling donor, currently there are open transplant protocols at Children’s of Alabama using matched unrelated donors. However, to be eligible for these types of transplant, patients have to meet certain eligibility requirements. These requirements are essentially markers of severe sickle cell disease, and may include a history of stroke, recurrent severe pain crises, or recurrent chest syndrome. Many sickle cell patients do well with current medical management strategies and do not require transplant, though roughly 10-15% of sickle cell patients do have severe complications and would meet these eligibility requirements. Nonetheless many do not come to transplant, in part due to our inability to locate matched unrelated donors in the NMDP registry. Unrelated cord blood transplantation has not been shown to be as effective as marrow transplantation due to a high rejection risk. Currently the only cord blood transplants being done in the US for sickle cell disease are those where the cord blood is from an HLA identical sibling. A potential barrier to transplanting sickle cell patients is the parent’s perception and fear that transplant could result in the death of their child. While this is true, current national data suggests that there is greater than 95% chance of survival following transplant using a matched sibling donor, and greater than 80% survival using a matched unrelated donor. In addition, it is well known that as sickle cell patients get older they develop more problems, making it harder for them to undergo transplant. Recently there has been a change in how we approach sickle cell transplants, and efforts are now being made to minimize toxicity of transplant using reduced conditioning preparative regimens. Dr. Hilary Haines, an Assistant Professor of Pediatrics, consults on most of the sickle cell patients being transplanted at Children’s of Alabama. She is also principle investigator for a national sickle cell bone marrow transplant study that utilizes a less intense conditioning regimen. In addition, in collaboration with Tim Townes, PhD, director of the Stem Cell Institute at UAB, Dr. Goldman is involved in basic laboratory research that uses a mouse model for sickle cell disease. Current laboratory studies are being undertaken using the sickle cell mouse model to try to identify agents other than chemotherapy that can be used in the transplant process that will make it safer. The focus is trying to find ways to open up the marrow space that will allow stem cells to more easily engraft. These preclinical studies are necessary to get these agents approved for human use.
“Fear of Transplant”
Most everyone is afraid of the word “transplant”, just as they are afraid of the word “cancer” and Dr. Goldman understands the devastation that hearing “You have cancer” or “You’re going to need a bone marrow transplant” can bring. “As both a parent and a healthcare provider, I understand it’s a lot to take in the first time,” he acknowledged. “I know that families and patients have a hard time absorbing the complexities of transplant, and when I first talk to them they are often shell shocked. I tell them that transplant is a complicated process that takes a great degree of preparation and planning, and that one cannot always predict what problems will be encountered. Sympathizing with his patients’ plight, Dr. Goldman offers encouragement, telling them transplant can feel like a marathon. “It’s a long race with many hills, ups and downs, feeling of exhaustion, and wanting to give up. But in the distance is the sight of the finish line, the cure, which makes it all worthwhile. Dr. Goldman understands the uncertainty patients and their families face when making the decision to transplant. “Some parents of children with leukemia understand that if transplant is recommended, despite its potential toxicity, it will give their child the best chance to survive. “[As such,] they are often willing to take that risk without hesitation. Other times it can be very challenging to convince families that transplant does in fact offer them the best chance for cure with good quality of life”. It is also true that outcomes for transplant, in general, are better than they were several years ago. There are several reasons for this, including better tissue typing, better anti-viral drugs, and improvements in our ability to monitor patient for complications.
Innocent victims of Cancer
Drawn to oncology for several reasons, Dr. Goldman really wanted to do something to advance the field of cancer. “Before medical school, I received a master’s degree in immunology and I wanted to combine that background with cancer,” he explained, “and bone marrow transplantation is the perfect combination of these fields.”
As a medical student in the 1980s, Dr. Goldman recalled being naturally drawn to Pediatrics. “I always loved kids, and was easily able to empathize with them and their families. Children so often seemed to be the innocent victims of their disease. By misfortune their diseases are often inherited, and in instances where they acquire a disease, such as cancer, it was not the consequence of an unhealthy life style”.
Despite the challenges encountered in the transplant world, Dr. Goldman appreciates the trust and care families place in him. “I’ve always considered it an honor to care for children and get them through what may very well be hardest time of their lives”.
Other articles in the Focus on Childhood Cancer Series:
In recognition of Childhood Cancer Awareness Month