Hematopoietic Stem Cell Transplantation

Published on 04/03/2015 by admin

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Hematopoietic Stem Cell Transplantation

Qaiser Bashir and Richard Champlin


Hematopoietic cell transplantation (HCT) is an effective treatment for a range of hematologic, immune, metabolic, and malignant diseases. HCT involves transfer of hematopoietic stem cells and immune cells from a donor to a recipient. Autologous transplants involve the collection of a patient’s own hematopoietic cells, cryopreservation of the cells, and later reinfusion after high-dose myelosuppressive or immunosuppressive therapy is conducted. Allogeneic HCT involves transplantation of cells from a healthy related or unrelated donor. Syngeneic transplants involve a genetically identical twin donor.

Autologous HCT

Autologous stem cell transplantation is primarily used in the treatment of malignancy. Many malignancies exhibit a dose-dependent response to myelosuppressive chemotherapy or radiation. Higher doses can induce a markedly greater antitumor response. Bone marrow suppression becomes the dose-limiting toxicity. A high-dose chemotherapy or radiation “preparative regimen” can be administered if it is followed by infusion of autologous hematopoietic stem cells to restore blood production and immunity. This approach is effective against a range of hematologic malignancies and select solid tumors.

Autologous stem cell transplantation is also a promising treatment for selected autoimmune diseases.1 High-dose therapy (HDT) is administered with the goal of ablating the autoreactive immune response and reconstituting immunity from stem cells.

Allogeneic HCT

Allogeneic HCT involves transplantation of cells from a healthy related or unrelated donor. Patients generally require treatment with an immunosuppressive preparative regimen (also referred to as conditioning) to prevent graft rejection and eliminate diseased hematopoietic cells. Some severely immunocompromised patients with severe combined immune deficiency may only require an infusion of healthy hematopoietic cells for effective treatment.

Allogeneic HCT can be used if the patient’s bone marrow is involved by the malignancy or damaged by the disease or prior therapy. Allogeneic HCT carries the risk of immune complications including graft rejection (a situation in which the recipient rejects the donor cells) or graft-versus-host disease (GVHD) (a situation in which the immune cells from the donor react against recipient tissues). Allogeneic HCT may also confer a beneficial immune-mediated graft-versus-malignancy effect in which donor immune cells react against residual malignant cells.2 Compared with autologous transplants, allogeneic HCT is generally more effective in eradicating malignancies, but it has a greater risk of treatment-related mortality as a result of GVHD and infections.


The incidence and severity of rejection and GVHD increase with greater genetic disparity between the donor and recipient, most notably if there is mismatching for human leukocyte antigens (HLA), the major histocompatibility complex in humans.

The HLA gene complex is located on the short arm of chromosome 6. The HLA region is subdivided into three regions: class I, class II, and class III. The class I region contains genes that encode the “classic” HLA antigens, HLA-A, HLA-B, and HLA-C, which are expressed on almost all nucleated cells of the body. The class II region contains genes that encode the HLA class II molecules HLA-DR, HLA-DQ, and HLA-DP. Class II genes are expressed constitutively in only a very restricted number of cell types that are specialized in antigen presentation, such as dendritic cells and B lymphocytes, but they can be induced on several other cell types. The class III region has no known HLA class I– and class II–like genes but includes a number of genes related to the immune response.

The best results of allogeneic hematopoietic transplantation have generally occurred with an HLA-identical sibling donor; however, most patients lack an HLA-identical sibling. Recent advances have markedly improved results with transplants from “alternative donors.”

An international network of registries to provide an HLA-matched unrelated donor has been established. More than 18 million potential donors can be accessed worldwide. Initial studies of unrelated donor transplants reported a relatively high rate of GVHD and treatment-related mortality. Improved results have been achieved with donors and recipients matched for HLA-A, HLA-B, HLA-C, and DRB1 using high-resolution (allele level) typing,3 and recent results with matched unrelated donor transplants are similar to those achieved with matched sibling donors.

Because of the tremendous polymorphism of the HLA gene complex, an HLA-matched unrelated donor can only be identified for about half of patients. Patients are most likely to match an individual from the same ethnic background, and persons with rare alleles or linkages and those from minority or mixed ethnicities are unlikely to have a matched unrelated donor available. Another limitation with transplantation from an adult unrelated donor is the time necessary to conduct the unrelated donor search and organize collection of the transplant from the donor.

Cell Sources for HCT

After HCT, hematopoiesis and immunity are predominantly derived from donor-derived hematopoietic stem cells, although mature T cells in the graft contribute to initial immune recovery. Human hematopoietic stem cells and progenitor cells are contained in the CD34+ fraction of bone marrow cells, which constitutes approximately 1% of the bone marrow. Bone marrow was initially the source of hematopoietic cells for transplantation, collected by multiple aspirations with the patient under general anesthesia. Hematopoietic cells also circulate in the peripheral blood, and their frequency increases after treatment with growth factors and after chemotherapy and peripheral blood progenitor cells can be used for transplantation. Larger numbers of CD34+ cells can generally be collected as peripheral blood progenitor cells, and hematopoietic recovery is accelerated with peripheral blood progenitor cell transplants compared with bone marrow; as a result, almost all autologous HCTs utilize peripheral blood progenitor cells. Several studies have compared the outcome of allogeneic HCT using bone marrow or peripheral blood progenitor cells. These studies uniformly show more rapid time to engraftment with peripheral blood progenitor cells but an increased risk of chronic GVHD (cGVHD). Some investigators have suggested superior disease-free survival (DFS) in matched siblings using peripheral blood progenitor cells,4 but in most studies, overall survival (OS) was similar. Bone marrow has produced improved outcomes compared with peripheral blood progenitor cells in children and in patients with aplastic anemia.

Umbilical cord blood is an alternative source of hematopoietic stem cells for transplantation. Cord blood units are obtained by collecting blood remaining in the umbilical cord and placenta after the delivery of an infant. Umbilical cord blood transplants are less likely to produce GVHD than are hematopoietic cells from adult donors, which allows successful transplants using unrelated units matched for four or five of the six HLA-A, HLA-B, and HLA-DR antigens.5 An international network of cord blood banks has been established, with collection of umbilical cord blood from volunteer unrelated donors after delivery of the newborn. Approximately 500,000 umbilical cord blood units are available worldwide. An umbilical cord blood unit provides a relatively low stem cell dose, which results in a slower pace of hematopoietic and immune recovery. Results are improved with higher cell doses and better HLA matching. Adequately matched umbilical cord blood units can be identified for most patients. Initial studies reported better results in children than in adults. A sufficient cell dose cannot be achieved with a single umbilical cord blood unit for most adult recipients; two umbilical cord blood units have been reported to improve outcomes and allow treatment of most adults. Centers focusing on this approach have reported results in children and adults similar to those obtained with matched bone marrow and peripheral blood progenitor cell transplants from unrelated adult donors. A recent registry analysis showed similar results with double umbilical cord blood transplants as with matched or one antigen mismatched unrelated donor peripheral blood progenitor cell transplants.6 Because the units are already collected and banked, umbilical cord blood transplants can generally be performed more rapidly than transplants from an unrelated adult donor.

Haploidentical relatives are another potential donor source. Parents, children, and half of siblings are haploidentical, and thus these donors are readily available for most patients. Several centers have reported success with transplantation of T-cell–depleted peripheral blood progenitor cells with a low rate of GVHD.7 These transplants are associated with a relatively high rate of rejection, slow immune recovery, and a substantial risk of treatment-related mortality. An alternative approach uses unmodified haploidentical bone marrow transplantation with posttransplant treatment with cyclophosphamide, tacrolimus, and mycophenolate; this regimen produces a low rate of severe acute and chronic GVHD and treatment-related morbidity and mortality.8

Recent multicenter studies confirm that successful transplants can be performed in children and adult recipients from either unrelated cord blood or a haploidentical related donor9; overall, results have been similar with each approach and comparable with those reported with matched unrelated donors. Further studies are required to directly compare these strategies and to optimize results of HCT from every donor source. Use of these alternative donors provides an opportunity for treatment of nearly all patients with a clinical indication for HCT. A comparison of different sources of hematopoietic stem cells is presented in Table 30-1.

Table 30-1

Comparison of Different Types of Allogeneic Transplantation

  Related Unrelated Cord Blood Haploidentical
Chances of finding a match 25% 50% 90% >95%
HLA-matching requirement Strict (8/8 is optimal; 1 mismatch may be feasible) Strict (8/8 is optimal; 1 mismatch may be feasible) Less strict (6/6 is optimal; 1 or 2 mismatches allowed) Less strict (matched at only one haplotype)
Banking needs Minimal* Minimal* Dedicated CB banks Minimal*
Time required 15-30 days 3-4 mo 15-30 days 15-30 days
Donor attrition Unlikely Likely Unlikely Unlikely
Donor safety Toxicity due to BM harvest or G-CSF Toxicity due to BM harvest or G-CSF None Toxicity due to BM harvest or G-CSF
Type of graft BM or PB BM or PB Cryopreserved CB BM or PB
Stem cell dose Standard Standard Low Standard
Graft manipulation TCD TCD None TCD
Conditioning Myeloablative conditioning or reduced- intensity conditioning Myeloablative conditioning or reduced- intensity conditioning Myeloablative conditioning or reduced- intensity conditioning Myeloablative conditioning or reduced-intensity conditioning
Engraftment Standard Standard Delayed Delayed
Treatment-related mortality Standard Standard High High
Risk of GVHD Standard Slightly high Low High
Availability of additional cells (DLI) Yes Yes None Yes
Immune reconstitution Standard Standard Delayed Delayed


BM, Bone marrow; CB, cord blood; DLI, donor-lymphocyte infusion; G-CSF, granulocyte colony-stimulating factor; GVHD, graft-versus-host disease; HLA, human-leukocyte antigen; PB, peripheral blood; TCD, T-cell depletion.

*Grafts are occasionally cryopreserved.

For the purpose of this table, results with a related donor transplant are considered standard.

Disease Indications for HCT

Allogeneic HCT can replace defective hematopoietic and immune cells with cells from a normal donor and is indicated to correct severe congenital and acquired bone marrow failure syndromes, metabolic disorders involving hematopoietic cells, and immune deficiency disorders. These disorders include aplastic anemia, hemoglobinopathies, and Fanconi anemia. HCT is also indicated for treatment of severe combined immunodeficiency and other severe immunodeficiency states.

This review focuses on HCT for treatment of cancer. HCT is performed for a wide array of hematologic malignancy and chemotherapy-sensitive solid tumors. Allogeneic HCT is associated with higher treatment-related mortality compared with autologous HCT, but it provides a graft that is free of disease, has a competent immune system, and confers the immune-mediated graft-versus-malignancy effect. Donor lymphocyte infusions (DLIs) can be given to augment this antitumor effect and may induce complete remission (CR) in selected patients with disease relapse after HCT.10

Several factors are considered when making a decision to perform HCT. A careful evaluation of available nontransplant treatment options is necessary. Communication barriers with the patients should be identified, and patients should be educated about their disease and the risks and potential benefits of HCT, as well as alternative forms of therapy. Once the decision is made to proceed with a transplant, a thorough assessment of factors such as the patient’s age, performance status, disease status, comorbidities, and financial and psychosocial support is necessary.

Because HCT is associated with significant morbidity and mortality, it is generally reserved for life-threatening diseases for which no other satisfactory treatment option exists. As new therapeutic options continue to evolve, so does the role of HCT. The indications for HCT vary by the disease type. Several organizations such as the European Blood and Marrow Transplantation11 and the National Comprehensive Cancer Network (www.nccn.org) have provided detailed treatment guidelines for specific diseases and clinical settings.

Malignant diseases constitute the most common indication for HCT. Generally, the malignancies that exhibit a marked dose response to myelosuppressive therapy are best treated with HCT. Use of myeloablative conditioning regimens prior to autologous HCT and allogeneic HCT provide the maximum disease response; however, long-term DFS and risk of relapse vary by disease type and status. The toxicity is generally high, particularly in elderly patients. In recent years, use of reduced-intensity conditioning has shown better tolerability and equivalent results to that seen with myeloablative-conditioning HCT. Reduced intensity conditioning HCT primarily relies on the graft-versus-tumor effect for maximal disease control. This approach has allowed transplants to be successfully performed in older patients and in persons with comorbidities that preclude a myeloablative-conditioning transplant.

The indications for HCT vary by disease type. Results are better in patients who have chemosensitive disease or are in remission. Outcomes of HCT are not favorable in patients with poor performance status and who have refractory or progressive disease. Evidence-based reviews have been published by the American Society for Blood and Marrow Transplantation regarding the role of blood and marrow transplantation in the treatment of selected disease.12 The numbers of patients receiving autologous and allogeneic transplantation for each major indication are shown in Figure 30-1.

Acute Myeloid Leukemia

Allogeneic HCT is an optimal treatment for appropriately selected patients with acute myeloid leukemia (AML).13 Some centers have also successfully used autologous HCT for patients with AML who are experiencing their first or second remission. Recent advances have allowed risk stratification of patients with AML based on cytogenetic and molecular abnormalities, and this risk stratification helps guide therapeutic decisions.14 HCT is not recommended for patients in the “favorable” category. Large metaanalyses have shown that availability of an HLA-matched sibling did not result in superior DFS or OS with allogeneic HCT performed in the first period of remission for patients with favorable cytogenetics, t(8;21), inv16, or t(15;17). HCT prolongs DFS in patients with “intermediate-risk” and “high-risk” disease. Patients with diploid cytogenetics are considered intermediate risk, but recent studies have identified prognostically important subgroups based on molecular abnormalities. A large donor versus no-donor analysis of patients with cytogenetically normal AML showed that patients with the prognostically adverse FLT3-internal tandem duplication had improved DFS with allogeneic transplantation.15 Patients with nucleophosmin (NPM1) or CEBPA mutations without FLT3-internal tandem duplication had a better prognosis with chemotherapy, and there was a similar outcome with HCT compared with standard chemotherapy. HCT can also result in long-term DFS in approximately one third of patients with primary refractory AML.

AML is most common in elderly persons. Reduced intensity conditioning HCT allows for successful transplantation in patients with AML who would otherwise be considered ineligible because of age or comorbidities. Disease relapse is an important concern after HCT. The prognosis of patients who relapse with AML after undergoing a transplant is poor. However, approximately 20% of patients with chemosensitive disease can achieve a durable remission with a second allogeneic transplant16 (see Chapter 98).

Myelodysplastic Syndromes

Allogeneic HCT is an established indication for the treatment of myelodysplastic syndromes (MDSs).17 An international prognosis scoring system (IPSS) is used to classify patients with MDS into low, intermediate-1, intermediate-2, and high-risk categories based on bone marrow blast percentage, karyotype, and cytopenias.18 A modification of the IPSS system that incorporates a larger number of cytogenetic abnormalities, IPSS-R, was recently presented.19

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