Hematopoietic Stem Cell Transplantation: BMT Grows Up

from Practice Update, Summer 2005

Karen Sommer in the Blood and Marrow processing lab.

By Roger Giller, MD, Director, Pediatric Bone Marrow Transplant Program, The Children’s HospitalChristine Rhodes, Director, Physician Relations, The Children’s Hospital

Hematopoietic stem cell transplantation (HSCT), often referred to as bone marrow transplantation (BMT), involves the intravenous infusion of stem cells to reestablish normal blood cell production following high doses of chemotherapy and/or radiation therapy. The first successful human bone marrow transplantations were performed in the 1960’s in Acute Lymphoblastic Leukemias (ALL) patients who received supralethal total body radiation. The technology associated with bone marrow transplantation subsequently has been expanded to include transplants that are either autologous (infusion of the patient’s own hematopoietic stem cells) or allogeneic (infusion of another individual’s hematopoietic stem cells). Different stem cell sources are also available for transplantation. These sources include bone marrow, peripheral blood and umbilical cord blood. Experts at The Children’s Hospital Center for Cancer and Blood Disorders in Denver , performed the region’s first cord blood transplant nine years ago, and lead the region in research related to HSCT. “The Center’s experience with unusual pediatric cancers and its relationship with other leading cancer centers allow for positive outcomes for patients treated in the Center. This results in referrals to us from throughout the Rocky Mountain region,” said Dr. Roger Giller, director of the pediatric BMT program and principal investigator, Children’s Oncology Group.

Certain advantages of peripheral blood and umbilical cord blood have led to increased use of these stem cell sources in recent years. Peripheral blood progenitor cells offer more rapid hematologic recovery, and thus require less supportive care post transplant than bone marrow transplants. One drawback of this stem cell source in allogeneic HSCT may be heightened risk of graft vs. host disease (GVHD). Umbilical cord blood provides an easily accessible, rich supply of hematopoietic stem cell precursors. Use of cord blood at times can be restricted due to limited cell doses available for large adolescent and adult patients.

Children’s BMT program has been certified as a national transplant center by the Children’s Oncology Group (COG), the Foundation for Accreditation of Cellular Therapy (FACT), the regulatory arm of the American Society of Blood and Bone Marrow Transplantation (ASBMT), and numerous national insurance providers. These certifications entail external review of the program’s procedures and outcomes by national experts in transplant.

The Children’s Hospital BMT Program interacts with numerous registries of bone marrow and umbilical cord blood.

These registries catalogue approximately six million potential unrelated donors worldwide for patients who lack suitably matched allogeneic family member donors. Children’s has its own marrow processing laboratory with a dedicated staff. This FDA registered facility has the capability of growing and manipulating heamatopetic stem cells. The hospital has a local partnership with the University of Colorado Cord Blood Bank —a collaboration which is unique in the region.

“In the University of Colorado Cord Blood Bank , cord blood is collected, catalogued and frozen—ready as a stem cell source for children receiving treatment at The Children’s Hospital Center for Cancer and Blood Disorders or elsewhere in the country or world. The expertise of the Cord Blood Bank allows exact dosage levels and combinations of cord blood from different donors for maximum effectiveness,” said Melissa Croskell, lead technician in The Children’s Hospital’s Blood and Marrow Processing Lab.

HSCT Now Standard Therapy

Hematopoietic stem cell transplantation is now considered standard therapy for a variety of cancers (leukemias, solid tumors), severe non-malignant blood disorders (aplastic anemia, sickle cell disease, thalassemia), and certain life-threatening genetic diseases (storage disorders, severe immunodeficiencies). Pediatric cancers managed with bone marrow transplantation include ALL, AML, CML, lymphoma, neuroblastoma, brain tumors and other solid tumors. In most of these instances, transplantation is recommended only in high risk situations where initial non-transplant therapy is expected to fail or cancer recurrence develops.

HSCT has also been used in sickle cell patients with history of stroke, recurrent acute chest syndrome, or recurrent painful crises. Also, children with ALL or AML with certain genetic features, such as the Philadelphia chromosome or Monosomy 7 are candidates for transplantation in first remission. The Children’s Hospital Center for Cancer and Blood Disorders recently collaborated on a study with Children’s Memorial Hospital in Chicago looking at the outcomes of HSCT in pediatric AML and Myelodysplasia patients with Monosomy 7. In children with chronic myelogenous leukemia and juvenile chronic myelomonocytic leukemia, HSCT is used as primary therapy since no other curative treatment exists. HSCT is also frequently considered after a relapse of ALL, AML or lymphoma.

The rationale for HSCT in cancer treatment is that high dose chemotherapy, often in combination with total body irradiation, may overcome cancer cell resistance and achieve additional tumor cell kill not possible with standard dose treatments. This strategy is only feasible when marrow toxicity from high dose chemotherapy can be circumvented by hematopoietic rescue. In allogeneic BMT, the additional benefit of graft vs. tumor (GVT) effect may occur. In GVT, donor lymphocyte cells attack the malignant cells of the recipient, producing additional tumor cell kill. In patients with nonmalignant hematopoietic disorders or immunodeficiencies, BMT replaces defective or absent blood-forming or lymphoid immune cells. Patients with storage disorders, such as Hurler’s disease, receive HSCT to provide appropriate enzyme-making macrophage cells to populate their tissues. These cells can help digest and remove damaging storage products.

A major challenge in performing allogeneic transplants is finding a closely matched sibling or unrelated donor. Donor/recipient matching is determined by tissue (HLA) typing, a special blood test. Also, sufficient recipient immune suppression must be achieved to prevent graft rejection and post-engraftment graft vs. host disease (GVHD). The primary obstacle in autologous transplantation is collecting sufficient hematopoietic progenitor cells that are not contaminated by tumor cells. In some instances, tumor cells can be purged from autologous stem cells by treating the cell graft with chemotherapy or antibodies. Children’s molecular Pathology Lab and the affiliated University of Colorado Health Sciences Center Cytogenetics Lab assist the processing lab in monitoring autologous stem cell products for tumor cell contamination using highly sensitive genetic techniques.

Treatment Phases and Recovery

There are four major treatment phases in transplantation:

• Preparative therapy
• Stem cell rescue
• Supportive care
• Long term follow-up

The preparative phase is designed to produce both immune suppression and anti-cancer effect. Preparative regimens utilize one or more chemotherapy drugs, often in combination with total body irradiation. Stem cell rescue is accomplished by the intravenous infusion of bone marrow, peripheral blood stem cells, or umbilical cord blood. Supportive care in the initial months post-transplant includes transfusions of red blood cells and platelets, and infection prevention and treatment. Therapy for prevention of GVHD is necessary in allogeneic transplants. Successful engraftment of transplanted stem cells usually occurs about 10-28 days following transplant. Peripheral blood stem cell transplant patients usually recover white cell counts earlier than patients receiving bone marrow or cord blood transplants. Platelet recovery generally occurs six or more weeks after HSCT. Hematopoietic growth factors such as G-CSF or GM-CSF may be used to speed blood count recovery. Children’s Blood Banks and Transfusion Medicine Service supports the blood product needs of the hospital’s BMT patients. The post-transplant period can be complicated by bacterial, viral, and fungal infections. Certain infections are typically seen at different time intervals after the transplant. The post-transplant period can be divided into an early phase (0-1 month), an intermediate phase (1-6 months), and a late phase (6-12 months) with respect to infectious risks. During the early phase, when the patient’s white count is extremely low and chemotherapy and radiation may have disrupted the mouth and GI tract lining, bacteria from the patient’s own respiratory and digestive tracts are common causes of infection. Antibiotics and intravenous gamma globulin decrease the risk of bacterial infection immediately following transplant. Fungal infections are also a serious potential problem in patients with low white counts or on immunosuppressive medications. To reduce the risk of fungal infection, patients receive preventive medications. The Children’s Hospital Center for Cancer and Blood Disorders’ physicians have vast resources available to assist them in treating side effects and complications; including over 600 physicians in virtually every pediatric specialty who stand ready to assist the team along with pediatric pharmacists, lab technicians and radiologists all practicing at one of the nation’s best children’s hospitals.

The Children’s Hospital BMT patients are hospitalized in a special BMT unit that utilizes state of the art construction technology to reduce infection. Patient rooms receive HEPA-filtered air under positive pressure to adjoining rooms and corridors. This fresh, filtered air is exchanged 30 times per hour. Rooms have private restroom and shower facilities and the unit has a dedicated playroom and family lounge. Patients must wear masks when outdoors and need to live in clean outpatient environments during the initial months post-transplant.

In the intermediate post-BMT phase (1-6 months after transplant), the patients have reduced lymphocyte numbers and function and, thus, are susceptible to viral infections including CMV, adenovirus, and RSV. Preventive administration of acyclovir or ganciclovir help reduce CMV and other herpesvirus infections (shingles, cold sores) in this post-transplant period. Avoidance of crowds and individuals with colds or flu reduces the risk of exposure to respiratory or gastroenteritis viruses. Other infections such as Pneumocystis carinii pneumonia are also a risk in this intermediate phase. Patients receive trimethoprim-sulfamethoxazole or pentamidine for prevention of pneumocystis. The Children’s Hospital Center for Cancer and Blood Disorders physicians work closely with the patient’s primary care physician (PCP) and referring specialist in this phase—understanding that during this time the BMT team becomes the primary medical contact for the family. Transcribed notes and medical summaries are available to PCP’s and telephone communication is welcome.

The late phase, 6-12 months post transplant, may be associated with infections from encapsulated bacteria such as pneumococcus due to reduced function of the spleen. Reactivation of the chicken pox virus as shingles is also common. Patients on prolonged immunosuppressive treatment for chronic GVHD have an increased and prolonged risk of infection. Post-transplant patients are encouraged to transition back to their referring hematologist/oncologist and PCP for routine medical care with the understanding that support from the BMT Team is only a phone call away. Approximately 20-70 percent of allogeneic bone marrow transplant patients experience some degree of acute GVHD. Factors influencing GVHD risk include the degree of HLA match, stem cell source, patient age, and donor sex. Acute GVHD occurs within the first 100 days after transplant. Manifestations include rash, diarrhea, and jaundice. Chronic GVHD occurs after day 100 and may involve multiple organ systems as well. Skin rash, weight loss, dry eyes, mouth sores, lung disease and abnormal liver function are common manifestations. Treatment for GVHD consists of further use of immunosuppressive drugs.

Families whose child is undergoing BMT are generally required to reside close to the transplant center for a 3-6 month period. This allows for frequent outpatient visits with The Children’s Hospital BMT Team until the child’s risk of infection improves and supportive care needs (transfusions, IV antibiotics, etc.) are reduced. For BMT families whose homes are more than one hour from the transplant center, special housing is required to provide a safe and understanding environment. This is where special facilities such as the Denver Ronald McDonald House and Brent’s Place fill a critical need along with The Children’s Hospital’s team of social workers and case managers who assist families with a smooth transition home.

Although HSCT has many challenges, it represents an important advance in curative treatment for a variety of serious pediatric illnesses. To reach a member of The Children’s Hospital Center for Cancer and Blood Disorders, call One Call at 720-777-3999 or 800-525-4871.