Richard W. Childs and Ramaprasad Srinivasan
Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic modality widely used in the management of some hematologic malignancies and a variety of nonmalignant disorders. Autologous HSCT typically involves administration of high-dose chemotherapy followed by infusion of hematopoietic stem cells procured from the recipient prior to ablative therapy. On the other hand, allogeneic HSCT involves infusion of hematopoietic stem cells from a related or unrelated human leukocyte antigen (HLA)-compatible donor, following myeloablative or reduced intensity conditioning (RIC) of the recipient.
AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION
Autologous hematopoietic stem cell transplantation (auto-HSCT) was developed to overcome the lethal hematopoietic toxicity associated with high-dose chemotherapy used to treat dose-responsive malignancies.1,2 A role for auto-HSCT has been clearly established in the management of multiple myeloma and aggressive non-Hodgkin lymphoma (NHL). Initial enthusiasm for this approach in solid tumors such as metastatic breast, ovarian, and lung cancer has been tempered by the failure of prospective randomized trials to demonstrate benefit over conventional treatments. The role of auto-HSCT continues to be explored in neuroblastoma and Ewing sarcoma.
General Considerations
Most auto-HSCTs are performed using peripheral blood stem cells (PBSCs) collected after mobilization with granulocyte colony-stimulating factor (G-CSF), with or without chemotherapy priming. Curative potential resides solely in the ability of high-dose chemotherapy to eradicate the underlying malignancy; no immune-mediated graft-versus-tumor (GVT) effects are generated. The high-dose chemotherapeutic regimen utilized is tailored to the malignancy being treated based on its chemosensitivity profile; for instance, melphalan (200 mg/m2) is the most widely used high-dose conditioning agent in patients with multiple myeloma undergoing auto-HSCT.
Infections related to chemotherapy-induced neutropenia and immunosuppression as well as extramedullary toxicities from high-dose chemotherapeutic agents account for the majority of complications occurring after auto-HSCT. There is a lower risk of treatment-related mortality (TRM) compared with allogeneic HSCT, typically less than 5% in most series.
Contamination of the stem cell product by malignant cells may limit the beneficial effects of high-dose chemotherapy. Efforts to purge tumor cells contaminating hematopoietic grafts by CD34+ cell selection or by in vitro incubation of the stem cell graft with cytotoxic drugs remain investigational and have met with only moderate success.
Results of Autologous Hematopoietic Stem Cell Transplantation
Autologous Hematopoietic Stem Cell Transplantation in Hematologic Malignancies
Multiple Myeloma Large phase II trials have demonstrated high response rates (complete response [CR] 30%–50%) and impressive disease-free survival (DFS) and overall survival (OS) rates (median, more than 5 years). Randomized phase III trials in relatively young patients (less than 65 years of age) have shown superior response rates, DFS, and OS for auto-HSCT versus conventional chemotherapy.3
Consecutive or tandem auto-HSCTs have been compared with single auto-HSCT in several randomized prospective studies. While some studies suggest improved DFS (but not OS) with the tandem approach, other large multicenter trials also indicated a survival benefit for tandem auto-HSCT. Subgroup analyses suggest that the survival benefit is most pronounced in patients who do not achieve a CR or a very good partial response following the first auto-HSCT.
Tandem auto-HSCT has also been compared with auto-HSCT followed by reduced intensity or nonmyeloablative allogeneic HSCT, with one randomized study demonstrating superior OS and progression-free survival (PFS) with the latter approach. However, a recent randomized trial conducted through the Clinical Trials Network (CTN) which enrolled over 700 subjects reported no difference in 3-year PFS and OS between patients receiving a tandem auto-HSCT versus a tandem auto/allotransplant, with significantly higher TRM being reported in the latter group.4
Auto-HSCT is currently considered standard first-line therapy for younger patients (up to age 65) with myeloma and results in long-term CR rates of 5% to 10%. Melphalan (200 mg/m2) is the most commonly used preparative regimen. The role of tandem auto-HSCT remains to be clearly defined, although some subgroups of patients appear to benefit from this approach. Due to recent data showing no clear survival benefit with an upfront auto/allogeneic transplant approach, as well as the advent of newer drugs such as lenalidomide, bortezomib, and carfilzomib which are highly active against myeloma, the role of allogeneic transplant in this disease remains investigational. Indeed, these agents have led to a reevaluation of the role of auto-HSCT in the management of this disease. Several ongoing studies are attempting to determine whether
newer anti-myeloma agents can supplant auto-HSCT as the standard of care in most patients;
integration of these agents in the management algorithm can potentiate or extend the benefits derived from auto-HSCT.
Emerging data suggest that bortezomib-based pretransplant induction therapy as well as post-transplant consolidation using a variety of strategies might improve overall outcome associated with auto-HSCTs.5
Lymphoma Lymphomas are among the most common indications for auto-HSCT. The benefit of auto-HSCT has been most clearly observed in chemosensitive Hodgkin’s disease and in intermediate- and high-grade NHL. Auto-HSCT results in improved event-free survival (EFS) and OS in patients with relapsed chemosensitive intermediate-/high-grade NHL, compared with conventional salvage therapy.6 Results from a randomized study suggest that initial treatment with auto-HSCT may benefit some patients with intermediate-/high-grade NHL, compared to standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).
Among Hodgkin’s disease patients, those with chemosensitive disease on first relapse have an improved EFS with auto-HSCT compared with standard salvage chemotherapy. Patients with primary progressive disease (those who progress on first-line chemotherapy) may also benefit from auto-HSCT as part of a salvage regimen.
Incorporation of therapeutic antibodies such as rituximab (anti-CD20) in first-line treatment regimens has significantly improved our ability to treat several subsets of NHL. The role of auto-HSCT in the era of B-cell–targeted monoclonal antibodies remains to be determined.
ACUTE MYELOID LEUKEMIA Auto-HSCT has been used both as postremission therapy in acute myeloid leukemia (AML) in first complete remission (CR1) and as therapy after relapse. Phase III studies in patients in CR1 suggest an improvement in DFS but not in OS, compared with conventional postremission therapy. Further studies are required to clarify which, if any, prognostic subgroups are likely to benefit from auto-HSCT.
Autologous Hematopoietic Stem Cell Transplantation in Solid Tumors
The knowledge that some malignancies exhibited dose-dependent responses to chemotherapy led to the investigation of high-dose chemotherapy followed by auto-HSCT in the treatment of solid tumors. Based on negative results from phase III trials, auto-HSCT has been largely abandoned in the management of some malignancies (particularly metastatic breast cancer) but remains under investigation in several other solid tumor types such as rhabdomyosarcoma.
Breast Cancer While promising results from phase II studies in patients with metastatic breast cancer paved the way for randomized phase III studies of auto-HSCT, these later larger studies failed to demonstrate an unequivocal benefit. At least seven large trials have compared auto-HSCT with standard chemotherapy in patients with metastatic breast cancer. Six demonstrated superior EFS with auto-HSCT, but none showed an OS advantage.7 Similar results were obtained in patients with high-risk breast cancer undergoing adjuvant auto-HSCT. Because of a lack of survival benefit and higher toxicity, there is little enthusiasm for further investigation of auto-HSCT in breast cancer.
Germ Cell Tumors Phase II trials of auto-HSCT in relapsed or refractory germ cell tumors have yielded response rates of 40% to 65% and long-term survival rates of 15% to 40%. Patients with progressive disease or human chorionic gonadotropin levels greater than 1,000 IU/L at transplantation, mediastinal primaries, and those refractory to cisplatin-based therapy have a worse outcome and may not benefit from auto-HSCT. An interim report from a European Group for Blood and Marrow Transplantation study suggested no advantage for auto-HSCT over standard salvage chemotherapy in patients failing cisplatin-based chemotherapy.
Auto-HSCT is considered an option for salvage of selected patients in first or subsequent relapse, although randomized phase III studies have failed to demonstrate unequivocal benefit for high dose over standard chemotherapy in this setting.8
There is no role for auto-HSCT in the initial management of germ cell tumors; several randomized phase III studies have demonstrated similar outcomes for conventional chemotherapy and auto-HSCT in patients with germ cell tumors with high-risk features.9
Other Tumors Available data do not suggest a clear benefit for auto-HSCT in ovarian and lung cancers. When administered after an initial course of standard induction chemotherapy, auto-HSCT appears to improve short-term DFS in high-risk neuroblastoma compared with conventional dose maintenance chemotherapy. However, a large randomized study was unable to demonstrate a survival advantage for patients undergoing auto-HSCT.
Some patients with Ewing sarcoma/primordial neurectodermal tumor and other soft tissue sarcomas may benefit from high-dose chemotherapy. In the absence of evidence to support a survival benefit, patients should be treated with auto-HSCT only in the setting of a clinical trial.
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Allogeneic HSCT can cure patients with advanced chemotherapy-resistant hematologic malignancies.10-12 The first successful allogeneic HSCTs in humans were reported in 1968. These transplants were performed in children with congenital immune deficiencies, using donor stem cells from HLA-compatible sibling donors. In the early years after the advent of allogeneic HSCT, immune deficiency syndromes and disorders of hematopoiesis constituted the major indications for the procedure. With a better understanding of the graft-versus-leukemia (GVL) effect and its curative potential, hematologic malignancies have now become the most common indication for an allogeneic HSCT. More than 25,000 allogeneic HSCTs are performed worldwide annually for a wide array of both malignant and nonmalignant disorders.
Indications for Allogeneic Hematopoietic Stem Cell Transplantation
Allogeneic HSCT has been used as a potentially curative treatment modality in both malignant and nonmalignant diseases (Table 18.1). Currently, the most common indication for an allogeneic HSCT (over 75%) is an underlying hematologic malignancy (acute and chronic myelogenous leukemia, acute lymphocytic leukemia, and NHL being the most common). Nonmalignant conditions that are potentially curable by HSCT include disorders of hematopoiesis (e.g., aplastic anemia [AA]), immunodeficiency syndromes (e.g., Chediak-Higashi disease and severe combined immunodeficiency syndrome), congenital disorders of erythropoiesis (e.g., thalassemias), and inborn errors of metabolism (e.g., mucopolysaccharidoses).13,14 The advent of new treatment options for certain diseases (such as the tyrosine kinase inhibitors targeting bcr/abl, which are effective in the treatment of chronic myelogenous leukemia) and improvements in the toxicity profile associated with HSCT are likely to alter the indications for allogeneic transplantation.
Antileukemic Potential of Allogeneic Hematopoietic Stem Cell Transplantation: Underlying Principles
In the 1960s and 1970s, allogeneic HSCT was largely viewed as a means of ensuring immunohematopoietic reconstitution or replacement after administration of high doses of chemotherapy with or without radiation. This premise still applies to the treatment of nonmalignant conditions, for which the major goal is to provide normal cellular components to replace or rectify an underlying deficiency. For hematologic malignancies, the dose-intensive preparative or conditioning regimen was initially considered to be critical for the eradication of the underlying malignancy, with HLA-matched donor stem cells used merely to reverse the accompanying fatal bone marrow (BM) ablation. However, over the last two decades, it has become increasingly evident that the ability to generate a donor immune-mediated antimalignancy effect, termed GVL or GVT, is critical for the successful eradication of malignancies after allogeneic HSCT. The following clinical observations have provided incontrovertible evidence for the existence of GVL and highlight the role of donor T lymphocytes in mediating this effect10-12,15-17:
Decreased risk of leukemia relapse in patients experiencing chronic graft-versus-host disease (GVHD).
Increased risk of leukemia relapse in patients undergoing T-cell–depleted transplants.
Increased risk of leukemia relapse in recipients of syngeneic as opposed to non-twin sibling donor allografts.
Ability of immunosuppression withdrawal and/or donor lymphocyte infusions (DLIs) to induce sustained remission in patients with chronic myeloid leukemia (CML) who relapse after transplantation.
Recognition of GVL has led to the development of RIC or nonmyeloablative conditioning regimens, in which efficacy is largely dependent on the generation of donor immune-mediated antitumor responses.
Planning Allogeneic Hematopoietic Stem Cell Transplantation
Allogeneic HSCT is a complex procedure requiring careful planning and a multidisciplinary approach to patient management. Factors including patient age, performance status, underlying disease, and donor availability need to be considered before decisions regarding the type of transplantation to be performed (e.g., conventional myeloablative versus nonmyeloablative) and GVHD prophylaxis regimen are made.
Evaluation of Transplant Recipients
The degree of donor–host HLA compatibility is one of the most important factors affecting outcome after HSCT. Evaluation of the transplant recipient begins with HLA testing and a search for an appropriate donor. The initial donor search focuses on identifying a sibling matched at the allele level for HLA-A, HLA-B, and HLA-DR loci. If a suitable sibling donor is not available, a search for an HLA-compatible unrelated donor or unrelated cord blood unit can be made through the National Marrow Donor Program (NMDP).
Table 18.1 Indications for Hematopoietic Stem Cell Transplantation
Acute Leukemias
Acute lymphoblastic leukemia (ALL)
Acute myelogenous leukemia (AML)
Chronic Leukemias
Chronic myelogenous leukemia (CML)
Chronic lymphocytic leukemia (CLL)
Juvenile chronic myelogenous leukemia (JCML)
Juvenile myelomonocytic leukemia (JMML)
Myelodysplastic Syndromes
Refractory anemia (RA)
Refractory anemia with ringed sideroblasts (RARS)
Refractory anemia with excess blasts (RAEB)
Refractory anemia with excess blasts in transformation (RAEB-T)
Chronic myelomonocytic leukemia (CMML)
Stem Cell Disorders
Aplastic anemia (severe)
Fanconi anemia
Paroxysmal nocturnal hemoglobinuria
Pure red cell aplasia
Myeloproliferative Disorders
Acute myelofibrosis
Agnogenic myeloid metaplasia (myelofibrosis)
Polycythemia vera
Essential thrombocythemia
Lymphoproliferative Disorders
Non-Hodgkin lymphoma
Hodgkin disease
Phagocyte Disorders
Chediak-Higashi syndrome
Chronic granulomatous disease
Neutrophil actin deficiency
Reticular dysgenesis
Inherited Metabolic Disorders
Mucopolysaccharidoses (MPS)
Hurler syndrome (MPS-IH)
Scheie syndrome (MPS-IS)
Hunter syndrome (MPS-II)
Sanfilippo syndrome (MPS-III)
Morquio syndrome (MPS-IV)
Maroteaux-Lamy syndrome (MPS-VI)
Sly syndrome, β-C glucuronidase deficiency (MPS-VII)
Adrenoleukodystrophy
Mucolipidosis II (I-cell disease)
Krabbe disease
Gaucher disease
Niemann-Pick disease
Wolman disease
Metachromatic leukodystrophy
Histiocytic Disorders
Familial erythrophagocytic lymphohistiocytosis
Histiocytosis-X
Hemophagocytosis
Inherited erythrocyte abnormalities
β-Thalassemia major
Sickle cell disease
Inherited Immune System Disorders
Ataxia-telangiectasia
Kostmann syndrome
Leukocyte adhesion deficiency
DiGeorge syndrome
Bare lymphocyte syndrome
Omenn syndrome
Severe combined immunodeficiency (SCID)
SCID with adenosine deaminase
Absence of T & B cells SCID
Absence of T cells, normal B cell SCID
Common variable immunodeficiency
Wiskott-Aldrich syndrome
X-linked lymphoproliferative disorder
Other Inherited Disorders
Lesch-Nyhan syndrome
Cartilage-hair hypoplasia
Glanzmann thrombasthenia
Osteopetrosis
Inherited Platelet Abnormalities
Amegakaryocytosis/congenital thrombocytopenia
Plasma Cell Disorders
Multiple myeloma
Plasma cell leukemia
Waldenstrom macroglobulinemia
Other Malignancies
Breast cancer
Ewing sarcoma
Neuroblastoma
Renal cell carcinoma
Adapted from the list of transplant indications provided by the National Marrow Donor Program (NMDP).
Thorough history and physical examination, with emphasis on the underlying diagnosis and its treatment, concomitant medical problems, performance status, transfusion history, and any history of opportunistic (particularly fungal) infections should be done. Assessment of major organ function, including pulmonary function testing and full cardiac evaluation, should be undertaken. Serologic testing to detect prior exposure to cytomegalovirus (CMV), herpes virus, Epstein-Barr virus (EBV), hepatitis viruses, HIV, toxoplasmosis, and varicella is also needed. Counseling is required to focus on the potential benefits and risks of transplantation, need for a dedicated caregiver, and, when appropriate, fertility prospects.
Identification of a Suitable Donor
Matched related donor: approximately one-third of patients screened will have a suitable HLA- compatible sibling donor. While donors with a less than complete (6/6) HLA match can be used, greater HLA disparity increases the risk of both graft rejection and GVHD.
Syngeneic donor: identical twin transplants are rarely performed because high degrees of histocompatibility (including for minor histocompatibility antigens) minimize clinically meaningful GVL effects. Syngeneic donors are most desirable in the transplantation of acquired nonmalignant diseases (such as severe aplastic anemia [SAA]) where GVL is not required.
Matched unrelated donor (MUD): There are more than 15 million donors in worldwide registries. Searches conducted through the NMDP in general will identify a suitable donor for approximately two-thirds of Caucasians, but for some minority groups, due to increased HLA diversity, it is much harder to find a match. The process should be initiated as early as possible because the time to transplant once a search is initiated is typically 3 to 4 months. For a given degree of donor–host HLA disparity, the risk of GVHD and graft rejection is higher with unrelated donors compared to related donors.
Haploidentical donor: most patients have a sibling, parent, or child with one matched HLA haplotype who could serve as donor. Transplants from haploidentical donors are associated with a higher incidence of GVHD, necessitating T-cell depletion in most circumstances to prevent life-threatening GVHD. Impaired immune reconstitution is common and leads to a high incidence of opportunistic infections in recipients of haploidentical transplants. Recent studies utilizing posttransplant cyclophosphamide as a method to induce in vivo T-cell depletion following the transplantation of either haploidentical BM or PBSCs have shown encouraging results, with one retrospective report of extremely low rates of acute GVHD and chronic GVHD with DFS and OS rates comparable to dual cord blood transplants.18 Based on these promising results, a randomized trial comparing cord blood transplantation with haploidentical BM transplantation with posttransplant cyclophosphamide has recently been initiated through the CTN.
Umbilical cord cells: blood collected from the placenta at the time of childbirth can be used as a source of hematopoietic stem cells. While umbilical cord transplants are associated with a lower incidence of GVHD (even with HLA mismatching), their widespread use is limited by an increased risk of graft failure due to the small numbers of stem cells harvested. Umbilical cord transplants were largely restricted to children and young adolescents. However, recent studies have established that umbilical cord transplants in adults are feasible. The use of dual cord units and ex vivo expansion of cord progenitor cells are some of the strategies being explored to boost the stem cell dose available for transplant. As of 2012, it is estimated that more than 600,000 cord blood units are available in the worldwide registry for public use.
Procurement of Hematopoietic Stem Cells
The majority of hematopoietic stem cells reside within the BM, which traditionally served as the source of the allograft. However, the availability of G-CSF, which mobilizes hematopoietic stem cells into the circulation, has led to the widespread use of PBSC allografts.
Obtaining stem cells from the BM involves multiple aspirations from the iliac crests, a relatively safe procedure performed under general anesthesia. Mobilized stem cells are typically collected from the peripheral blood by apheresis after administration of G-CSF (10 to 15 μg/kg/day) for 4 to 6 days. G-CSF mobilized PBSC grafts usually contain higher numbers of CD34+ progenitor cells as well as T cells (CD3+ cells) compared with BM grafts.
Compared with BM stem cells, transplants using PBSCs are associated with faster neutrophil and platelet engraftment, a reduction in transfusion requirements, and a similar incidence of acute GVHD, although chronic GVHD occurs with higher frequency with the use of PBSC compared with BM transplants.19 Some studies have shown that in patients with an underlying hematologic malignancy, PBSC transplants from HLA-identical siblings are associated with a survival advantage compared with BM transplants. However, a recent multicenter trial conducted through the CTN that randomized more than 500 patients with hematologic malignancies to either a BM or a PBSC transplant from an unrelated donor reported no difference in relapse, DFS, or OS between the two approaches with recipients of PBSC transplant having a significantly higher incidence of debilitating extensive chronic GVHD.20These data suggest that for patients with hematologic malignancies undergoing a MUD transplant, BM may be the preferred stem cell source.
Nevertheless, given the ease of stem cell collection from both the practitioner and the donor perspectives, the higher progenitor cell yield, earlier engraftment, and a lower risk of graft failure, the majority of allogeneic HSCTs worldwide in adults currently employ mobilized peripheral blood as a source of hematopoietic stem cells.
Conditioning Regimen
A variety of conditioning regimens have been used in allogeneic HSCT. The choice of conditioning regimen for a given patient is dictated by the underlying disease, the age of the patient, the presence of medical comorbidity, and donor characteristics (especially the degree of HLA compatibility). Table 18.2 lists some commonly used conditioning regimens.
Conventional or Myeloablative Conditioning
Myeloablative conditioning regimens serve a dual purpose:
High doses of chemotherapy with or without radiation provide tumor cytoreduction, usually accompanied by eradication or ablation of host hematopoietic function.
Suppression of the host’s immune system, a prerequisite for preventing rejection of the transplant.
The burden of tumor eradication in conventional transplants rests on both the transient cytoreductive properties of the conditioning agents and on more durable GVL effects mediated by donor immune cells.
The two most commonly used regimens are cyclophosphamide in combination with either total body irradiation (TBI) or busulfan. TBI-based regimens have a higher incidence of secondary malignancies, growth retardation, thyroid dysfunction, and cataracts, while non-TBI regimens, particularly those containing busulfan (oral or intravenous), are associated with more veno-occlusive disease (VOD) and mucositis. The advent of intravenous busulfan, with its more predicable pharmacokinetic profile, has allowed more consistent exposure to busulfan and a reduction in the incidence of VOD. The underlying condition often dictates the optimal conditioning regimen. For example, patients with acute lymphoblastic leukemia (ALL) appear to have a lower risk of relapse with TBI-based regimens, which are therefore preferentially used for this indication.
Reduced Intensity Conditioning Reduced intensity preparative regimens were devised in an effort to minimize conditioning-related morbidity associated with conventional transplants, while retaining the host immunosuppression necessary to ensure engraftment. Reduced intensity preparative regimens that do not eradicate host hematopoiesis are also referred to as nonmyeloablative conditioning regimens.
The burden of tumor eradication in reduced intensity transplants rests mainly on the donor immune-mediated GVL effect. These regimens are associated with a lower incidence of some conditioning-related toxicities (VOD, mucositis, prolonged neutropenia, etc.).
Reduced intensity regimens are better tolerated by older patients (up to 70 years) and by those with medical comorbidities and have allowed allo-HSCT to be extended to these populations. Several transplant centers are currently evaluating reduced intensity transplantation in patients with hematologic malignancies, solid tumors, and nonmalignant hematologic disorders. Although the risk of TRM appears lower with RIC regimens, several retrospective studies have suggested the risk of disease relapse in malignant diseases such as myeloma, and myelodysplastic syndrome (MDS) may be higher with this approach compared with conventional myeloablative transplants.
Results of Allogeneic Hematopoietic Stem Cell Transplantation
Allogeneic HSCT is the only curative option for many patients with hematologic malignancies: 85% to 90% of all allogeneic transplants in the United States are undertaken for this indication.
Chronic Myeloid Leukemia
CML is a myeloproliferative disorder characterized by the presence of a characteristic t(9;22) (q34;q11) translocation, the Philadelphia chromosome. The natural history consists of a relatively indolent chronic phase with progression to the more aggressive accelerated phase and blast crisis. Although allogeneic HSCT is the only proven curative therapy for this condition, the introduction of targeted agents with remarkable efficacy (such as imatinib mesylate, dasatinib, and nilotinib) has led to the acceptance of these agents as standard initial therapy for patients with chronic phase CML. Consequently, allo-HSCT is usually reserved for patients with accelerated phase or blast crises CML and for chronic phase patients who have failed agents targeting the abl kinase.
Among chronic phase patients undergoing transplantation from an HLA-compatible sibling, 65% to 80% are cured; similar results are now being reported in patients undergoing MUD transplantation. Early results in patients receiving RIC are promising, but prospective studies are needed to determine if this approach is equivalent to conventional allo-HSCT. Transplantation is much less effective in accelerated phase or blast crisis (where cure rates are 10%–20%).
Younger patients and patients who undergo transplantation within a year of diagnosis have the best outcomes. Chronic phase CML is sensitive to GVL effects and a single DLI can reinduce remission in 70% of patients who relapse after transplantation, as can withdrawal of immunosuppression (such as cyclosporine) used for GVHD prophylaxis/treatment. Chronic phase CML patients who fail to achieve a cytogenetic remission with imatinib can be successfully salvaged with allo-HSCT, as shown in a recent study.
Acute Myeloid Leukemia
The indication and timing for transplantation in AML and outcome after allogeneic HSCT depend on the risk category.
Patients with intermediate or poor prognosis AML as determined by cytogenetics are at high risk for relapse after chemotherapy and should be evaluated for allogeneic HSCT in CR1 when an HLA-matched sibling donor is available. Recent studies have also shown that patients with normal cytogenetics who have an FLT3-ITD, or a wild-type NPM1 or CEBPA without an FLT3-ITD, are also at increased risk for relapse and may benefit from an allogeneic transplant in CR1. 21
Patients transplanted in CR1 have a 45% to 60% probability of long-term DFS.
Patients transplanted in first relapse or after induction of second complete remission (CR2) have only a 22% to 40% chance of long-term DFS.
Outcomes after transplantation in first relapse or CR2 are comparable.
Allogeneic HSCT in good-prognosis AML is usually reserved for CR2 or first relapse, because the risk of TRM outweighs the benefits from early transplantation (CR1) in this group.
Less than 20% of patients with primary induction failure or those beyond CR2 have durable leukemia remission after allogeneic HSCT.
Acute Lymphoblastic Leukemia
While a significant proportion of childhood ALL is curable with chemotherapy, the majority (60%–70%) of adults with this disease relapse following initial chemotherapy. Patients older than 60 years of age, those with a leukocyte count higher than 30,000/μL, or with high-risk cytogenetics [t(4;11), t(1;19), t(8;14), or t(9;22)] have a particularly poor prognosis. Traditionally, allogeneic HSCT in CR1 has been recommended for adult patients with ALL with poor prognostic features (DFS rates in the range of 40%–60%), reserving transplant for patients without adverse factors for CR2 (DFS rates of approximately 40%). However, a recent randomized trial showed patients with standard-risk ALL who received upfront allogeneic transplant in CR1 had a survival advantage compared with patients who received consolidative chemotherapy reserving transplant for CR2.22 Therefore, allogeneic transplant in CR1 is a reasonable strategy to prevent disease relapse in adults with either standard-risk or high-risk ALL.
Myelodysplastic Syndrome
Allogeneic HSCT offers a 30% to 40% probability of long-term DFS in patients with MDS. The two most important factors predicting outcome after transplantation are blast percentage and cytogenetic risk group. Accordingly, patients with few blasts (refractory anemia or refractory anemia with ringed sideroblasts) have 50% to 75% long-term DFS, while more advanced stages (e.g., refractory anemia with excess blasts) are associated with a 30% DFS. Similarly, patients with good-risk cytogenetics have an approximately 50% probability of DFS compared with 10% or less for those with poor-risk cytogenetics. Nonetheless, allogeneic HSCT remains the only curative therapy for MDS and should be considered a potential definitive therapy. Reduced intensity HSCT is associated with a higher risk of relapse in MDS patients than is conventional HSCT and should be reserved for patients who are not candidates for myeloablative HSCT or performed as part of well-designed trials.
Non-Hodgkin’s Lymphoma
Low-Grade Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia Experience with allogeneic HSCT in low-grade lymphomas and CLL is largely restricted to patients undergoing the procedure late in the course of their disease after multiple chemotherapeutic options have been exhausted; 50% to 65% of patients will achieve long-term DFS. The typically indolent disease course and profound susceptibility to GVL makes low-grade lymphomas and CLL amenable to management and cure using nonmyeloablative conditioning approaches. Remarkably, several studies have shown that more than
40% of patients with 17p deletion CLL, who have the worst prognosis with conventional chemotherapy, can obtain long-term DFS with a reduced intensity transplant. These findings have led to an increased use of upfront transplantation in this high-risk CLL cohort.23
Aggressive Non-Hodgkin Lymphoma The role of allogeneic HSCT in patients with intermediate- and high-grade lymphomas is unclear. Most studies have reported a high incidence of TRM with myeloablative transplantation in this group. As a consequence, allogeneic HSCT that uses RIC is generally reserved for those patients in whom potentially curative autologous HSCT has failed or for those unlikely to benefit from an autologous transplant (patients with chemotherapy-resistant disease).
Multiple Myeloma
TRM rates in the range of 50% have discouraged the use of conventional myeloablative transplantation for multiple myeloma. Nevertheless, there is evidence that donor immune-mediated graft-versus-myeloma effects can be curative. Recently, RIC has been explored as a safer transplant approach to treat multiple myeloma. TRM has been reported to be significantly lower (less than 25%) compared with historic myeloma cohorts undergoing myeloablative conditioning; importantly, graft-versus-myeloma effects resulting in durable disease remission can be induced after reduced-intensity transplants. Autologous transplantation as myeloma cytoreduction followed by nonmyeloablative allogeneic transplantation as immunotherapy to eradicate minimal residual disease appears promising, with DFS of more than 50% in some studies. However, a recent randomized trial conducted through the CTN group which enrolled over 700 subjects reported no difference in 3-year PFS and OS between patients receiving a tandem auto transplant versus a tandem auto/allotransplant with significantly higher TRM being reported in the latter group.4
Aplastic Anemia
Allogeneic HSCT can cure SAA.24 Early studies of allogeneic HSCT in patients with SAA showed a high incidence of graft rejection (up to 35% in some early series) and GVHD. Sensitization to histocompatibility antigens as a result of multiple transfusions and the use of cyclophosphamide alone as pretransplant conditioning accounted for these high rejection rates. Subsequent approaches added antithymocyte globulin to cyclophosphamide to minimize graft rejection while preventing severe and potentially lethal GVHD. Additionally, the routine use of leukocyte-depleted and irradiated blood products has decreased the risk of graft rejection to less than 5% in most studies. A combination of cyclosporine A (CSA) and methotrexate is generally used as GVHD prophylaxis with delayed and gradual withdrawal of immunosuppression to minimize the risk of GVHD. Patients under the age of 40 years receiving an allogeneic HSCT from an HLA-matched sibling have an excellent chance for cure, with long-term survival rates approaching 90% in children. Several studies indicate that transplant outcomes are better in patients with AA when BM is used as the primary graft source, rather than PBSCs, since the latter is associated with an increased incidence of chronic GVHD.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation
Complications of allogeneic HSCT are most commonly related to preparative regimen toxicities, infections occurring as a consequence of immunosuppression, or acute or chronic GVHD.
Conditioning-related Toxicities
Conditioning-related toxicities vary depending on the type and dosage of agents used in the preparative regimen. Nausea, vomiting, and mucositis occur commonly with myeloablative preparative regimens. Busulfan tends to be associated with more severe mucositis.
Hemorrhagic cystitis occurring early in the course of transplantation is usually associated with preparative regimens containing high-dose cyclophosphamide. In contrast, hemorrhagic cystitis more than 72 hours after conditioning is typically viral (polyoma virus BK or adenovirus). Attention to hydration and the routine use of 2-mercaptoethanesulfonate has virtually eliminated cyclophosphamide- associated hemorrhagic cystitis.
Opportunistic infections occur with conditioning-related neutropenia. Bacteria and fungi that are normally present in the skin, gastrointestinal (GI) tract, or respiratory tract cause the majority of these infections.
Damage to gut mucosa and indwelling venous catheters serve as the portal of entry for most life-threatening gram-negative or aerobic gram-positive organisms. The use of Prophylactic oral antibiotics such as quinolones for gut decontamination has decreased the incidence of gram-negative bacteremia without impacting survival. Routine use of these agents should be weighed against the increased risk of gram-positive bacteremia and emergence of resistant gram-negative strains.
Candida and Aspergillus fungal infections occur commonly during conditioning-induced neutropenia. Prophylactic fluconazole appears to protect against sensitive Candida. In a recent phase III randomized trial, prophylactic voriconazole was associated with a trend toward a lower incidence of invasive fungal infection compared with fluconazole, although OS was similar in the two groups.25
VOD is characterized by the triad of jaundice, tender hepatomegaly, and ascites occurring early posttransplant. Risk factors include
Advanced age.
Conditioning with busulfan, with up to 30% of patients receiving oral busulfan developing this complication. The advent and preferential use of IV busulfan appears to have led to a decrease in the incidence of VOD.
Preexisting liver disease.
Development of acute GVHD.
Transplants from matched unrelated and haploidentical donors.
Prophylaxis with oral ursodiol may protect against this complication. VOD can be severe and life threatening in approximately 25% of patients developing this complication. Treatment remains largely supportive, although defibrotide and recombinant tissue plasminogen activator have each been used with some success in severe VOD. In a recently reported randomized phase III study in pediatric patients undergoing HSCT, defibrotide prophylaxis was associated with a lower incidence of VOD.26
Graft-versus-Host Disease
GVHD is one of the most common complications of allogeneic HSCT. GVHD is a consequence of allogeneic donor T cells damaging normal recipient tissues. Based on the time of onset, clinical features, and pathophysiology, GVHD is classified as either acute or chronic.27
Acute Graft-versus-Host Disease Acute GVHD typically commences during the first 100 days after transplantation. Of HLA-matched sibling donor transplant recipients, 20% to 50% experience acute GVHD; the incidence is higher in transplants utilizing unrelated or partial HLA-matched related donors. The extent of donor–host HLA disparity, recipient age, T-cell content of the graft, intensity of the conditioning regimen, and the type of GVHD prophylaxis regimen utilized all influence the incidence and severity of GVHD.
The skin, GI tract, and liver are the most common targets of alloreactive donor T cells causing GVHD. The following clinical and laboratory features should arouse suspicion of GVHD:
Skin: erythematous maculopapular rash frequently involving the palms and soles. Severe cases can present with skin desquamation.
GI: crampy abdominal pain, and large-volume watery diarrhea characterize GVHD of the colon and distal small bowel. In severe cases, bloody diarrhea or ileus may occur. Anorexia, dyspepsia, weight loss, and nausea and vomiting are characteristic of upper GI GVHD.
Hepatic: elevated alkaline phosphatase and direct bilirubin with or without elevations in transaminases characterize acute GVHD of the liver.
Definitive diagnosis can be difficult because a variety of other conditions (such as drug-induced skin rash, viral colitis) can present with similar features. Biopsy and histopathologic examination of involved tissue is considered the gold standard for diagnosing GVHD.
GVHD is a major contributor to TRM; strategies directed at preventing this complication are an important aspect of transplant planning. Pharmacologic prophylaxis and graft T-cell depletion are established methods that effectively reduce the incidence and severity of GVHD. CSA or tacrolimus combined with methotrexate or mycophenolate mofetil are commonly used for GVHD prophylaxis. Effective T-cell depletion of the allograft can be achieved in vitro by CD34+ cell selection or in vivo pharmacologically (alemtuzumab or posttransplant cyclophosphamide). However, T-cell–depleted transplants are associated with a higher risk of graft failure, leukemia relapse, and opportunistic viral infections. Selective depletion of alloreactive T cells and T-cell–depleted transplants with scheduled T-cell add back 30 or more days following transplantation have been shown to reduce the incidence of GVHD without compromising GVL.
Treatment of established GVHD depends on the type and severity of involved organs (for grading of acute GVHD, see Table 18.3). While mild (grade I) skin GVHD can be managed effectively with topical corticosteroids, visceral GVHD and more severe forms of cutaneous GVHD require systemic immunosuppressive therapy. Glucocorticoids (methylprednisone, typically at doses of 1 to 3 mg/kg/day) are the mainstay of therapy and are given in conjunction with cyclosporine or tacrolimus, with doses titrated to maintain therapeutic serum levels. Unfortunately, only approximately 50% of patients demonstrate durable responses to this form of therapy (for treatment of established acute GVHD, see Table 18.4).
Nonresponding or steroid-refractory patients have a poor outcome, with mortality rates more than 80%. The majority developing steroid-refractory GVHD die from infectious complications or organ damage related to relentless immune attack. Comprehensive management of steroid-refractory GVHD patients with immunosuppressive agents such as daclizumab or infliximab accompanied by targeted infectious prophylaxis against enteric bacteria and Aspergillus appears to be a promising strategy that deserves further study (see Table 18.4).28
Chronic Graft-versus-Host Disease The onset of chronic GVHD is usually between 100 days and 2 years after transplantation. It affects 20% to 50% of recipients of allogeneic BM transplants and up to 80% receiving an allogeneic PBSC transplant. Risk is increased by
Prior history of acute GVHD.
Older patient age.
Use of HLA-mismatched or unrelated donors.
DLI administration.
Use of PBSC (as opposed to BM) allografts.
Table 18.4 Treatment of Acute Graft-versus-Host Disease: The National Heart, Lung, and Blood Institute Approach
Initial Management
Grade I GVHD (Stage 1–2 Skin)
Topical corticosteroid therapy
Grade II–IV GVHD
Management of Steroid-Refractory GVHD
(GVHD not responsive to 6 or more days of continuous therapy with ≥1 mg/kg methylprednisolone)
(A) Treatment
(B) Supportive care
GI, gastrointestinal; GVHD, graft-versus-host disease; IV, intravenously; NPO, nothing by mouth.
Patients may present with a myriad of clinical features including lichenoid or sclerodermatous skin changes, elevated liver function tests, xerostomia, dry eyes, diarrhea, weight loss, bronchiolitis obliterans, and thrombocytopenia with or without pancytopenia.
Most clinicians use a two-stage staging system: limited GVHD, representing localized skin involvement and extensive GVHD, which includes patients with more diffuse skin involvement or involvement of other target organs. Investigators at the National Institute of Health (NIH) have recently proposed a system for the diagnosis and classification of chronic GVHD based on histopathologic, clinical, laboratory, and radiologic features which rates chronic GVHD as mild, moderate, or severe.29
Therapy typically consists of cyclosporine or tacrolimus given in conjunction with low-dose corticosteroids. Alternative agents include mycophenolate mofetil, thalidomide, photochemotherapy with oral methoxypsoralen therapy followed by ultraviolet-A photophoresis, and monoclonal antibodies directed against T or B lymphocytes or cytokines implicated in pathogenesis.
A high risk of bacterial infections in patients with chronic GVHD warrants routine use of antibiotic prophylaxis against encapsulated bacteria and opportunistic pathogens.
Pulmonary Complications
Pulmonary complications may occur both early and late after transplantation, and they may be infectious or noninfectious in etiology.
Pulmonary Complications Attributable to Infections Fungi (Aspergillus and other agents) as well as viruses (CMV, respiratory syncytial virus, influenza, parainfluenza, etc.) can cause life-threatening pneumonia in the posttransplant setting. Early diagnosis, prophylactic or preemptive therapy (e.g., ganciclovir or foscarnet for CMV antigenemia), and prompt institution of definitive therapy when available are the major principles guiding management of these complications. The risk of Pneumocystis jiroveci pneumonia is greatest in the first 6 months after transplantation, particularly in patients receiving T-cell–depleted grafts or those suffering from chronic GVHD; prophylaxis with sulfa/trimethoprim or inhaled pentamidine virtually eliminates this complication.
Idiopathic interstitial pneumonitis usually occurs early after transplantation and is characterized by fever, hypoxia, and diffuse pulmonary infiltrates. TBI or drugs with pulmonary toxicity (i.e., busulfan) in the preparative regimen increase the risk of this complication. An infectious etiology as well as diffuse alveolar hemorrhage should be excluded before a diagnosis of idiopathic interstitial pneumonitis can be rendered. Corticosteroids and tumor necrosis factor–α antagonists have been used to treat this condition with modest results.
Diffuse alveolar hemorrhage is a relatively infrequent but often fatal complication of allogeneic HSCT. It is characterized by the rapid onset of dyspnea, cough, and hypoxia with diffuse bilateral infiltrates on radiography. High-dose corticosteroids and recombinant activated factor VII (Novo7) may be of therapeutic benefit, although the condition is lethal in 40% to 80% of cases.
Infectious Complications
Recipients of allogeneic HSCT continue to be at risk for infections beyond the period of conditioning-related neutropenia, with viral and fungal pathogens and encapsulated bacteria posing the greatest hazard.30 Factors influencing infectious risk include the presence of acute or chronic GVHD, the extent of immunosuppressive pharmacotherapy in the posttransplant period, T-cell depletion of the graft, and the use of cord blood transplants or partial HLA-mismatched or unrelated donors.
Bacterial Infections
Gram-negative bacteremia associated with GI GVHD and venous catheter-related infections (predominantly gram-positive pathogens) occur with greatest frequency during the first 3 to 4 months after transplantation.
Recurrent sinus and pulmonary infections are associated with chronic GVHD. Antibiotic prophylaxis against encapsulated organisms, using penicillin or an appropriate alternative, reduces the risk of these infections.
Patients with recurrent infections and low serum immunoglobulin levels may benefit from prophylactic intravenous immunoglobulin (IVIG) infusions.
Fungal Infections
Fungal infections constitute a major cause of mortality after allogeneic HSCT: 60% to 70% of patients developing invasive fungal infections die despite antifungal therapy.
Yeast (Candida species) and molds (Aspergillus) account for the majority of opportunistic fungal infections in the posttransplant period.
Candida infections typically occur early in the course of transplantation, often near the end of the neutropenic phase. Candidal infections can manifest as mucocutaneous candidiasis, candidemia, or with visceral involvement (the liver and spleen are most commonly involved). Routine prophylaxis with fluconazole or echinocandins offers protection against sensitive strains of Candida.
Invasive Aspergillus infections typically involve the lungs, paranasal sinuses, and the central nervous system (CNS), although dissemination to other visceral organs has been described. Predisposing factors are
Corticosteroids.
Severe GVHD.
The use of non–HLA-identical and unrelated stem cell donors.
Transplantation in rooms lacking laminar air flow.
Invasive fungal infections are difficult to eradicate. Fluconazole or echinocandins may be effective against sensitive Candida strains (like Candida albicans). Amphotericin B, lipid formulation amphotericin, echinocandins (caspofungin, micafungin, etc.), voriconazole, and posaconazole have demonstrated efficacy against Aspergillus and a wide spectrum of Candida species.
The diligent application of preventive measures such as avoiding the indiscriminate use of corticosteroids remains the most effective strategy for minimizing mortality related to invasive fungal infections.
Viral Infections
Cytomegalovirus While advances in screening and preventive therapy have reduced CMV-related mortality, CMV infection continues to be a major contributor to posttransplant morbidity. CMV is a DNA virus belonging to the herpes virus family. Posttransplant CMV infection is most often a consequence of viral reactivation in patients with prior exposure to CMV and is observed in 50% to 70% of CMV seropositive recipients. Reactivation typically occurs in the first 100 days after transplantation. Primary infection in CMV-seronegative recipients can follow transplantation from a seropositive donor. Acquisition of primary infection from CMV-positive transfusion products has been all but eliminated with routine use of leukocyte-depleted or CMV-negative blood products.
GVHD, the use of T-cell–depleted allografts, cord blood transplants, and the use of immunosuppressive agents such as alemtuzumab, corticosteroids, or calcineurin inhibitors increase the risk of CMV reactivation.
Interstitial pneumonitis is the most common and serious manifestation of CMV disease, followed by enteritis/colitis. Other manifestations include febrile episodes and marrow suppression resulting in thrombocytopenia with or without neutropenia. Mortality rates with CMV pneumonitis range from 65% to 85%. Ganciclovir or foscarnet given in conjunction with IVIG improves outcome associated with CMV disease (Table 18.5). Early detection methods utilize polymerase chain reaction (PCR) for viral DNA in the blood which predicts the subsequent development of CMV disease.
Preemptive therapy with ganciclovir or foscarnet (see Table 18.5) begun when CMV reactivation is first detected (either PCR or immunofluorescence assay) has dramatically reduced the incidence of CMV pneumonitis/enteritis and consequently CMV-related mortality. Newer approaches to the treatment of or prophylaxis against CMV disease include adoptive transfer of ex vivo expanded CMVspecific cytotoxic T lymphocytes.
Table 18.5 Surveillance and Management of Cytomegalovirus:The National Heart, Lung, and Blood Institute Approach
Surveillance
(CMV PCR)
Management of CMV Antigenemia*
Induction: Ganciclovir 5 mg/kg IV q12h or foscarnet 90 mg/kg IV q12h or valganciclovir 900 mg PO twice daily × 7 d,* followed by
Maintenance: Ganciclovir 5 mg/kg IV every day 5 times/week (M–F) or foscarnet 90 mg/kg IV every day 5 times/week (M–F) or daily valganciclovir 900 mg PO every day × 7 d
Management of CMV Disease†
Induction: Ganciclovir or foscarnet IV (at induction doses) q12h × 14 d and IVIg 500 mg/kg IV QOD × 14–21 d
Maintenance: Ganciclovir 5 mg/kg IV every day × 30 d
*If PCR shows two consecutive increases in copy number, continue induction and consider other treatment options (e.g., switching from ganciclovir to foscarnet) until PCR turns negative.
†Foscarnet may be the drug of choice in patients who have cytopenias and CMV reactivation or CMV disease.
CMV, cytomegalovirus; IV, intravenously; IVIg, intravenous immunoglobulin; PCR, polymerase chain reaction; PO, orally.
Epstein-Barr Virus–Associated Lymphoproliferative Disorder
EBV-related lymphoproliferative disorder is a B-cell malignancy arising as a consequence of impaired T-cell immunity against EBV. It is a relatively rare complication, affecting approximately 1% of all allogeneic transplant recipients, although certain transplants (especially T-cell depleted or umbilical cord blood) are associated with a significantly higher risk. The natural course of untreated EBV-related lymphoproliferative disorder is rapid progression, culminating in death. Allograft T-cell depletion, transplants from HLA-mismatched and unrelated donors or cord blood transplants, and the use of immunosuppressive agents predispose to the development of this malignancy.
Treatment with a monoclonal antibody to CD20 (rituximab), DLIs, withdrawal of posttransplant immunosuppression, or adoptive infusion of EBV-specific cytotoxic T cells are all effective in eradicating this disease, particularly when combined with withdrawal of immunosuppression.
Other Viral Infections Patients undergoing allogeneic HSCT are at risk for infectious complications associated with the herpes viruses, varicella zoster, and various respiratory viruses (respiratory syncytial virus, influenza, and parainfluenza). Adenoviruses or polyoma virus BK may appear clinically as hemorrhagic cystitis. Because cellular immunity is impaired in the posttransplant setting, otherwise self-limiting viral infections can have fatal sequelae. Recently, the investigational agent CMX-001 has shown promising activity in patients with systemic adenoviral infection.
Graft Failure
Graft failure is the inability to achieve (primary) or maintain (secondary) persistent donor hematopoiesis. Graft failure mediated by the recipient immune system is referred to as graft rejection. Graft failure is relatively uncommon in patients undergoing transplantation from an HLA-identical sibling donor (less than 2%). T-cell depletion, the use of HLA-mismatched or unrelated donor grafts, cord blood transplants, and pretransplant HLA alloimmunization caused by repeated transfusions are factors that increase the risk of graft rejection.
In myeloablative HSCT, primary graft failure presents as persistent pancytopenia (more than 3 to 4 weeks) after conditioning and is associated with a high mortality rate. Secondary graft failure is characterized by initial recovery of blood counts followed by a later loss of donor hematopoiesis.
Up to 50% of patients with graft rejection can be salvaged by repeat conditioning or immunosuppression (e.g., OKT3 plus corticosteroids) followed by reinfusion of a T-cell–replete allograft. Graft failure can also result from infections, drugs, or chronic GVHD. Patients can often be salvaged with hematopoietic growth factors (e.g., G-CSF) with or without additional stem cells.
Late Sequelae of Transplantation
Secondary Malignancies In addition to EBV-related lymphomas, leukemias and solid tumors can complicate allogeneic HSCT. The risk of solid tumors in transplant survivors at 10 years increases eightfold compared to age-matched controls. Melanomas, tumors of the oral cavity, bone, liver, CNS, and thyroid are some commonly encountered secondary malignancies. Younger patient age at transplantation and TBI-based conditioning regimens predispose to the development of secondary solid tumors.
Other Late Complications Growth retardation, infertility, restrictive pulmonary disease, cataracts, endocrine dysfunction, avascular necrosis of bones, osteopenia, and neurocognitive defects are other delayed sequelae of allogeneic HSCT.
Reduced Intensity and Nonmyeloablative Hematopoietic Stem Cell Transplantation
The high risk of TRM with conventional transplants and the appreciation that GVL effects can cure some hematologic malignancies provided the impetus for the development of reduced intensity and nonmyeloablative conditioning regimens.31,32 The basic principles underlying these regimens include the following:
RIC to induce adequate host immunosuppression for donor allograft “take” while minimizing toxicities related to dose-intensive conditioning.
Manipulation of posttransplant immunosuppression and administration of DLIs to promote rapid transition to complete donor immunohematopoiesis.
Reliance on the GVL effect for eradication of the underlying malignancy.
A variety of different conditioning regimens have been used, and the cumulative experience from various transplant centers has led to the following observations:
Toxicities such as VOD and mucositis are absent or mild compared to myeloablative transplants.
TRM is substantially lower (7%–20%) than the 25% to 40% mortality associated with standard or myeloablative transplants.
The improved toxicity profile has expanded the eligibility of allogeneic transplantation to older patients (up to 70 years of age) and patients with comorbid medical conditions.
GVL effects against several hematologic malignancies including AML, CML, ALL, CLL, NHL, and myeloma have been observed. However, at least in some malignancies (e.g., MDS, myeloma), the risk of relapse following RIC appears to be higher than that following myeloablative transplantation. Prospective randomized comparisons are required to determine if relapse risk and outcome in individual malignancies can be adversely affected by using RIC.
Pilot trials of nonmyeloablative HCT in solid tumors have shown for the first time the ability of the GVT effect to induce disease regression in treatment-refractory metastatic solid tumors. Renal cell carcinoma provides the best example of a tumor that may be susceptible to GVT effects33; GVT effects have also been described in other solid tumors including breast, pancreatic, colon, and ovarian carcinoma.34
Alternative Donor Transplantation
Transplantation from Matched Unrelated Donors
A 6/6 HLA-matched sibling donor can be identified for less than a third of patients evaluated for an allogeneic HSCT. Suitable volunteer donors registered with the NMDP can be identified for many patients who do not have a matched sibling donor but are otherwise considered candidates for an allogeneic HSCT. It is estimated that up to 70% of Caucasians will have at least one HLA-matched donor available. It may be more difficult to find appropriately matched donors for patients belonging to some racial/ethnic subgroups.
Outcome following matched unrelated HSCT has improved significantly with the introduction of routine molecular typing of HLA loci (as opposed to serologic typing) to identify donor–host compatibility. Transplantation using donors who are HLA-identical at the HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ loci by high resolution molecular typing (i.e., a 10/10 match) leads to outcomes approaching that following matched sibling transplants; however, GVHD remains a problem in unrelated donor transplants and contributes to worse overall outcome.
Transplantation from Mismatched Related Donors
Siblings with mismatches at one or more HLA loci can be used as donors for allogeneic HSCT. However, the incidence of both graft failure and GVHD is higher in recipients of partially matched sibling transplants.
Haploidentical transplants utilize parents, siblings, or children who share one haplotype with the recipient as donors. The high risk of lethal GVHD accompanying haploidentical transplantation mandates extensive T-cell depletion of grafts (either ex vivo of the allograft itself before infusion or in vivo using T-cell–depleting agents such as alemtuzumab or posttransplant cyclophosphamide). In addition, strategies such as the use of high CD34+ cell dose and/or nonmyeloablative conditioning have been utilized in attempts to improve outcome in transplants using partially matched, related donors. Donor– host killer immunoglobulin-like receptor (KIR) incompatibility may affect outcome following haploidentical transplantation. Specifically, transplants in which recipient cells do not express HLA molecules that can inhibit donor KIR are associated with a lower risk of GVHD and disease relapse, notably in patients with myeloid malignancies.35 Current evidence suggests that natural killer cell alloreactivity may mediate both the heightened GVL effects and reduced GVHD incidence in KIR-incompatible haploidentical transplants. This observation may allow selection of donors who are KIR mismatched in a bid to maximize NK alloreactivity.
Umbilical Cord Transplants
Cord blood, collected from peripartum placenta, contains stem cells with remarkable proliferative capability and is being used increasingly as an alternative source of stem cells for allogeneic HSCT. Both their proliferative potential and their relatively immature lymphocyte content (which would be predicted to lead to a lower incidence of GVHD) are viewed as advantages over other alternative stem cell sources such as haploidentical and unrelated donors. Furthermore, since umbilical cord allografts are derived from previously collected and stored cord blood, they are more readily available than unrelated donor grafts which involve donor preparation and collection of stem cells once a suitable donor is identified. The major limitation of cord blood as a source of hematopoietic stem cells (particularly in adults) is the relatively small number of cells that can be obtained from single cord blood units. A minimum of 2.5 × 107 nucleated cells/kg and/or ≥1.2 × 105 CD34+ cells/kg are required to obtain acceptable engraftment rates.
Early studies of cord blood transplants in children established the feasibility of this procedure, with acceptable engraftment rates (85% in one study) and low rates of acute GVHD (<10% in matched cord blood transplants).36Retrospective analyses comparing cord blood transplants to unrelated donor marrow transplants have since been undertaken and indicate the following37,38:
Cord blood transplants are typically associated with delayed hematopoietic recovery (median neutrophil recovery time of 27 days and median platelet recovery time of 60 days in one study), leading to a higher risk of infectious complications.
A lower incidence of acute GVHD as well as chronic GVHD is encountered following cord blood transplants.
TRM, disease relapse rates, and DFS following cord blood transplants are comparable to that seen in transplants using mismatched unrelated donor marrow.
The simultaneous use of multiple cord blood units (from different donors), the co-infusion of cord units with CD34+ selected haploidentical stem cells, and ex vivo expansion of cord blood stem cells are being explored as means of overcoming the limitations imposed by low stem cell dose and it is hoped that these approaches will allow more adults to undergo this procedure.39,40
References