General Information About Hematopoietic Cell Transplantation (HCT)
Rationale for HCT
Blood and marrow transplantation (BMT) or HCT is a procedure that involves infusion of cells (hematopoietic stem cells; also called hematopoietic progenitor cells) to reconstitute the hematopoietic system of a patient. The infusion of hematopoietic stem cells generally follows a preparative regimen given to the patient consisting of agents designed to do the following:
- Create marrow space.
- Suppress the patient's immune system to prevent rejection.
- Intensively treat malignant cells in patients with cancer.
HCT is currently used in the following three clinical scenarios:
- Treatment of malignancies.
- Replacement or modulation of an absent or poorly functioning hematopoietic or immune system.
- Treatment of genetic diseases in which an insufficient expression of the affected gene product by the patient can be partially or completely overcome by circulating hematopoietic cells transplanted from a donor with normal gene expression.
Autologous Versus Allogeneic HCT
The two major transplant approaches currently in use are autologous (using the patient's own hematopoietic stem cells) and allogeneic (using related or unrelated donor hematopoietic stem cells). Autologous transplant treats cancer by exposing patients to mega-dose (myeloablative) therapy with the intent of overcoming chemotherapy resistance in tumor cells, followed by infusion of the patient’s previously stored hematopoietic stem cells. It has also been used to attempt to reset the immune system in severe autoimmune disorders. In order for autologous transplant to work, the following must apply:
- The higher chemotherapy/radiation therapy dose that can be used because of hematopoietic stem cell support achieves a significantly higher cell kill of the disease. This may include increased tumor kill in areas where standard-dose chemotherapy has less penetration (central nervous system).
- Meaningful percentages of cure or long-term remission from the disease must occur without significant nonhematopoietic toxicities that would otherwise limit the therapeutic benefit achieved.
Allogeneic transplant approaches to cancer treatment also may involve high-dose therapy, but because of immunologic differences between the donor and recipient, an additional graft-versus-tumor (GVT) or graft-versus-leukemia (GVL) treatment effect can occur. Although autologous approaches are associated with less short-term mortality, many malignancies are resistant to mega-dose therapy alone and/or involve the bone marrow, thus requiring allogeneic approaches for optimal outcome. Current pediatric indications for autologous transplant include patients with certain lymphomas, neuroblastoma, and brain tumors.
Determining When HCT is Indicated: Comparison of HCT and Chemotherapy Outcomes
Because the outcomes using chemotherapy and HCT treatments have been changing with time, regular comparisons between these approaches should be performed to continually redefine optimal therapy for a given patient. For some diseases, randomized trials or intent-to-treat using a human leukocyte antigen (HLA)-matched sibling donor have established the benefit of HCT by direct comparison.[1,2] However, for very high-risk patients such as those with early relapse of ALL, randomized trials have not been feasible because of investigator bias.[3,4] In general, HCT approaches offer benefit only to children at high risk for relapse with standard chemotherapy approaches. Accordingly, treatment schemas that accurately identify these high-risk patients and offer HCT if reasonably HLA-matched donors are available have come to be the preferred approach for many diseases. Less well-established, higher-risk approaches to HCT (HLA haploidentical or significantly mismatched donors) are generally reserved for only the very highest-risk patients.
When comparisons of similar patients treated with HCT or chemotherapy are made and when randomized or intent-to-treat studies are not feasible, the following issues should be considered:
- Remission status: Comparisons between HCT and chemotherapy should include only those who obtain remission, preferably after similar approaches to salvage therapy, because patients failing to obtain remission do very poorly with any therapy. To account for time-to-transplant bias, the chemotherapy comparator arm should only include patients who maintained remission until the median time to HCT. The HCT comparator arm should also only include patients who achieved the initial remission mentioned above and maintained that remission until the time of HCT.
- Therapy approaches used for comparison: Comparisons should be made with the best or most commonly used chemotherapy and HCT approaches utilized during the time frame under study.
- HCT approach: HCT approaches that are very high risk or have documented lower rates of survival (i.e., haploidentical approaches) should not be combined for analysis with standard-risk HCT approaches (matched sibling and well-matched unrelated donors).
- Criteria for relapse: Risk factors for relapse should be carefully defined, and analysis should be based on the most current knowledge of risk. One should avoid combining high- and intermediate-risk patient groups because a benefit for HCT in the high-risk group can be masked when outcomes are similar in the intermediate-risk group.
- Selection bias: Attempts should be made to understand and eliminate or correct for selection bias. Examples include the following:
- Higher-risk patients preferentially undergoing HCT (i.e., patients who take several rounds to achieve remission or who relapse after obtaining remission and go back into a subsequent remission prior to HCT).
- Sicker patients deferred from HCT because of comorbidities.
- Patient/parent refusal.
- Lack of or inability to obtain insurance approval for HCT.
- Lack of access to HCT owing to distance/inability to travel.
One source of bias difficult to control for or detect is physician bias for or against HCT. The effect of access to HCT and therapeutic bias on outcomes of pediatric malignancies where HCT may be indicated has been poorly studied to date.
- Matthay KK, Villablanca JG, Seeger RC, et al.: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med 341 (16): 1165-73, 1999. [PUBMED Abstract]
- Woods WG, Neudorf S, Gold S, et al.: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission. Blood 97 (1): 56-62, 2001. [PUBMED Abstract]
- Lawson SE, Harrison G, Richards S, et al.: The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study. Br J Haematol 108 (3): 531-43, 2000. [PUBMED Abstract]
- Gaynon PS, Harris RE, Altman AJ, et al.: Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children's Oncology Group study CCG-1941. J Clin Oncol 24 (19): 3150-6, 2006. [PUBMED Abstract]
- Schrauder A, von Stackelberg A, Schrappe M, et al.: Allogeneic hematopoietic SCT in children with ALL: current concepts of ongoing prospective SCT trials. Bone Marrow Transplant 41 (Suppl 2): S71-4, 2008. [PUBMED Abstract]
- Pulsipher MA, Peters C, Pui CH: High-risk pediatric acute lymphoblastic leukemia: to transplant or not to transplant? Biol Blood Marrow Transplant 17 (1 Suppl): S137-48, 2011. [PUBMED Abstract]