General Information About Hematopoietic Stem Cell Transplantation (HSCT)
Rationale for HSCT
Blood and marrow transplantation, or HSCT, is a procedure that involves infusion of hematopoietic stem cells (along with hematopoietic progenitor cells) to reconstitute the hematopoietic system of a patient. The infusion of hematopoietic stem cells generally follows a preparative regimen consisting of agents designed to do the following:
- Create marrow space.
- Suppress the patient's immune system to prevent rejection.
- Eradicate malignant cells in patients with cancer.
HSCT is currently used in the:
- Treatment of malignancies,
- Replacement or modulation of an absent or poorly functioning hematopoietic or immune system, or for the
- Treatment of certain genetic diseases. In these cases, insufficient expression of the affected gene product can be partially or completely overcome by circulating hematopoietic stem cells transplanted from a donor with normal gene expression.
This summary focuses on the use of HSCT in the treatment of childhood malignancies.
Autologous Versus Allogeneic HSCT
The two major HSCT approaches currently in use are the following:
- Autologous (using the patient's own hematopoietic stem cells).
- Allogeneic (using related- or unrelated-donor hematopoietic stem cells).
An autologous transplant treats cancer by exposing patients to high-dose therapy with the intent of overcoming chemotherapy resistance in tumor cells, followed by infusion of the patient's previously stored hematopoietic stem cells. The transplant can be performed in a single procedure or tandem sequential procedures.
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 or graft-versus-leukemia treatment effect can occur. Although autologous approaches are associated with less short-term mortality, many malignancies are resistant to even high doses of chemotherapy and/or involve the bone marrow, thus requiring allogeneic approaches for optimal outcome.
Determining When HSCT Is Indicated: Comparison of HSCT and Chemotherapy Outcomes
Because the outcomes using chemotherapy and HSCT treatments have been changing over time, these approaches should be compared regularly to continually redefine optimal therapy for a given patient. For some diseases, randomized trials or intent-to-treat trials using an HLA-matched sibling donor have established the benefit of HSCT by direct comparison.[1,2] However, for very high-risk patients, such as those with early relapse of acute lymphoblastic leukemia, randomized trials have not been feasible because of investigator bias.[3,4]
In general, HSCT typically benefits only children at high risk of relapse with standard chemotherapy approaches. Accordingly, treatment schemas that accurately identify these high-risk patients and offer HSCT if appropriate allogeneic donors are available are the preferred approach for many diseases. Less well-established, higher-risk approaches to HSCT, such as haploidentical transplantation, are generally reserved for only the very highest-risk patients. However, these higher-risk approaches are becoming safer and more efficacious and are increasingly used interchangeably with fully matched allogeneic approaches.[6,7,8,9] (Refer to the Haploidentical HSCT section of the PDQ summary on Pediatric Allogeneic Hematopoietic Stem Cell Transplantation for more information.)
When comparisons of similar patients treated with HSCT or chemotherapy are made in the setting where randomized or intent-to-treat studies are not feasible, the following issues should be considered:
- Remission/disease status: Comparisons of HSCT and chemotherapy should include only patients who obtain remission, preferably after similar approaches to salvage therapy, because patients who fail to obtain remission do very poorly with any therapy.
To account for time-to-transplant bias, the chemotherapy comparator arm should include only patients who maintained remission until the median time to HSCT. The HSCT comparator arm should also include only patients who achieved the initial remission mentioned above and maintained that remission until the time of HSCT.
High-risk and intermediate-risk patient groups should not be combined because a benefit of HSCT in the high-risk group can be masked when outcomes are similar to those achieved in the intermediate-risk group.
- Therapy approaches used for comparison: Comparisons should be made with the best or most commonly used chemotherapy and HSCT approaches used during the time frame under study.
- HSCT approach: HSCT approaches that are very high risk or have documented lower rates of survival should not be combined for analysis with standard-risk HSCT approaches.
- Criteria for relapse: Risk factors for relapse should be carefully defined, and analysis should be based on the most current knowledge of risk.
- Selection bias: Attempts should be made to understand and eliminate or correct for selection bias. Examples include the following:
- Higher-risk patients preferentially undergoing HSCT (i.e., patients who take several rounds to achieve remission or who relapse after obtaining remission and go back into a subsequent remission before HSCT).
- Sicker patients deferred from HSCT because of comorbidities.
- Related to the time-to-transplant bias noted above, patients who undergo HSCT after relapse or recurrence are a subset of all patients with a disease recurrence and will be selected from those who are able to obtain a remission and remain healthy enough to undergo HSCT.
- Patient or parent refusal.
- Lack of or inability to obtain insurance approval for HSCT.
- Lack of access to HSCT because of distance or inability to travel.
Physician bias, for or against HSCT, is difficult to control for or detect. The effects of access to HSCT and therapeutic bias on outcomes of pediatric malignancies for which HSCT may be indicated have been poorly studied.
For more information about pediatric HSCT, refer to the following PDQ summaries:
- Pediatric Autologous Hematopoietic Stem Cell Transplantation.
- Pediatric Allogeneic Hematopoietic Stem Cell Transplantation.
- Pediatric Chimeric Antigen Receptor (CAR) T-Cell Therapy.
- Complications, Graft-Versus-Host Disease, and Late Effects after Pediatric Hematopoietic Stem Cell Transplantation.
- 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.
- 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.
- 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.
- 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.
- Merli P, Algeri M, Del Bufalo F, et al.: Hematopoietic Stem Cell Transplantation in Pediatric Acute Lymphoblastic Leukemia. Curr Hematol Malig Rep 14 (2): 94-105, 2019.
- Bertaina A, Merli P, Rutella S, et al.: HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. Blood 124 (5): 822-6, 2014.
- Handgretinger R, Chen X, Pfeiffer M, et al.: Feasibility and outcome of reduced-intensity conditioning in haploidentical transplantation. Ann N Y Acad Sci 1106: 279-89, 2007.
- Huang XJ, Liu DH, Liu KY, et al.: Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant 38 (4): 291-7, 2006.
- Luznik L, Fuchs EJ: High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res 47 (1-3): 65-77, 2010.
- 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.