Sarah Nikiforow, Thomas R. Spitzer
INTRODUCTION
Bone marrow or hematopoietic cell transplantation (BMT or HCT) is a potentially curative therapy for a wide variety of life-threatening congenital and acquired hematopoietic stem cell disorders and neoplastic diseases. With the development of human leukocyte antigen (HLA) typing to identify suitably matched donors, advances in tolerability and efficacy of conditioning regimens, improvements in supportive care, and advances in the prophylaxis and treatment of graft-versus-host disease (GVHD), clinical HCT became a reality. Many of the initial clinical HCT efforts were directed toward severe aplastic anemia and acute leukemia (which remains the paradigm for allogeneic HCT in adults). However, the demonstration of lasting donor lymphohematopoietic reconstitution, the powerful cytoreductive effect of intensive pretransplantation conditioning therapy, and the exploitation of a potent immunologically-mediated graft-versus-tumor (GVT) effect led to the successful application of HCT as up-front and salvage therapy for the many hematologic malignancies and other disorders shown in Table 38-1. Some applications of HCT are potentially curative, e.g., allogeneic transplantation for acute myeloid leukemia (AML). In other settings, HCT is primarily utilized to lengthen disease-free intervals without expectation of cure, e.g., autologous transplantation for multiple myeloma. In parallel with the above advances, the use of hematopoietic cell transplantation has expanded yearly. In 2009, more than 26,000 transplants were performed worldwide, over 15,000 of these being allogeneic HCTs (1).
TABLE 38-1 HEMATOPOIETIC STEM CELL TRANSPLANTATION: SELECTED INDICATIONS
The principal functions of HCT are to provide:
1. Rescue (i.e., by the infusion of pluripotent hematopoietic progenitor cells in the setting of cytoreductive chemotherapy that eradicates malignant cells but also ablates stem cells and other hematopoietic bone marrow elements)
2. Replacement (i.e., of a diseased hematopoietic stem cell population by healthy stem cells capable of regeneration of multiple hematopoietic lineages)
3. An immunologic platform (As mixed lymphohematopoietic chimerism often occurs after less intensive conditioning, HCT may be envisioned as creating an immunologic platform for adoptive cellular therapy. Subsequent manipulation may occur through donor lymphocyte infusions (DLI), expansion, or depletion of T-cell subsets (e.g., regulatory T cells), or selection of NK and dendritic cell subsets in order to augment GVT effects while minimizing GVHD) (2).
DONOR ORIGIN OF HEMATOPOIETIC STEM CELLS
• Autologous HCT or “high-dose chemotherapy with autologous stem cell rescue” refers to the collection from and subsequent reinfusion of hematopoietic progenitor cells into a patient with a solid or hematopoietic malignancy. Preparative intensive-conditioning therapy is given in an effort to reduce the number of malignant cells or to achieve immunoablation in a refractory autoimmune disease. Infusion of the patient’s own hematopoietic cells follows in order to rescue the patient from the negative effects of myeloablation, namely unacceptable levels of subsequent infectious and hematologic complications.
• Allogeneic HCT refers to the rescue and replacement of hematopoietic stem cells from an HLA-matched or partially matched donor source different from the patient. Allogeneic HCT may occur after myeloablative, reduced-intensity, or nonmyeloablative conditioning therapy. In addition to the cytoreductive effects of the preparative therapy, allogeneic HCT confers a potentially potent immunologically mediated response of donor immune cells against host tumor cells (i.e., a GVT effect induced by the interaction of donor T cells with host minor or major histocompatibility antigens or tumor antigens).
STEM CELL SOURCES FOR ALLOGENEIC HCT
Preference has historically been given to “matched” related donors (MRD) who are HLA-identical to the recipient, as determined by molecular class I and II HLA typing. As each sibling inherits two haplotypes, one from each parent, there is a 25% chance that any two full siblings will be genotypically identical. Only 30% of patients will have a matched sibling donor. Therefore, alternative, non-HLA-identical related and unrelated donor sources have been increasingly utilized, now enabling the majority of those without sibling donors to undergo HCT. Because of the increasingly varied sources of progenitor cells transplanted, hematopoietic cell transplantation (HCT) is a more representative term than BMT to describe the current field. Stem cell sources include:
• HLA molecularly “matched” unrelated donors (MUD)
• Unrelated donors molecularly “mismatched” at one or more HLA molecules (MMUD)
• Haploidentical-related donors (i.e., children or siblings, sharing only one inherited HLA haplotype)
• Partially HLA-matched umbilical cord blood (UCB)
Hematopoietic progenitor cells capable of restoring hematopoiesis and immune function following transplantation can be procured from:
• Bone marrow (BM; following a bone marrow harvest procedure in the operating room).
• Peripheral blood (PB; following “mobilization” with chemotherapy and/or recombinant hematopoietic growth factor(s) and/or CXCR4 antagonists followed by “collection” by pheresis).
• Umbilical cord (UCB; following full-term delivery) Given longer times to engraftment and higher rates of infectious complications with use of a single cord, the use of two umbilical cord blood units partially matched to each other is now common in adult HCTs.
CD34, a surface glycoprotein expressed on a small percentage of bone marrow cells is typically employed as a surrogate immunophenotypic marker for the pluripotent hematopoietic stem cell. Suitable numbers of CD34-expressing cells are needed in progenitor cell products to ensure acceptable kinetics of engraftment and sustained hematologic recovery following transplantation. Doses of more than or equal to 2 × 106/kg CD34-expressing progenitor cells are typically required in autologous or adult allogeneic donor products. Requirements are approximately one log lower for umbilical cord products.
PRETRANSPLANT CONSIDERATIONS
Designing an HCT approach for a particular patient requires consideration of the underlying disease and the recipient’s medical comorbidities, in addition to details of the transplant itself (3).
• Disease state: The achievement of disease control is a significant if not the dominant determinant of overall survival in most studies and is usually pursued maximally prior to transplantation. For example, according to outcomes analyses from the Center for International Bone Marrow Transplant Registry (CIBMTR), a patient with AML in first complete remission who undergoes an allogeneic transplant from a matched related donor has a 3-year survival probability of 53% compared with a patient with AML not in remission, whose 3-year survival probability is 24% (1).
• Recipient: Morbidity and mortality can also arise from transplant-related complications including organ failure secondary to the conditioning regimen, bacterial or viral infections, and both acute and chronic GVHD (in the allogeneic setting) or their treatments. These can lead to peritransplant mortality rates in the range of 1%–5% after autologous HCT and 10%–40% after allogeneic HCT. In recent years, the number and age of eligible recipients have increased significantly through the use of non-myeloablative and reduced-intensity conditioning regimens with associated lower rates of nonrelapse mortality. In analyses of reduced-intensity conditioning regimens, age per sehas not been shown to correlate with worse outcomes, and in 2009 more than 30% of allogeneic stem cell transplantations (SCTs) were performed in recipients over the age of 50, even in patients into their seventies (1). In contrast, performance status and comorbidities, specifically pulmonary, cardiac, and hepatic function, have been shown to have an important impact on nonrelapse mortality based on several validated scoring systems in both myeloablative and nonmyeloablative settings (4). Nevertheless, even after successful transplantation, life expectancy, immune function, and quality of life of recipients remain lower than that of age-matched peers.
PREPARATIVE THERAPY AND DONOR SELECTION
Choices of intensity of the conditioning regimen, donor, and type of stem cell source are driven not just by age and availability but more importantly by: (1) the status and nature of the underlying malignancy, (2) the combination of host comorbidities and treatment toxicities, (3) the reliance on GVT effect needed to prevent relapse in each case, and (4) the desire to avoid complications of GVHD.
• Intensity of the conditioning regimen: The options for intensity of conditioning regimens have diversified significantly in the last few years, expanding the eligible recipient pool but also increasing potential confusion over classification. One consensus scheme identifies myeloablative (MA) regimens as those that cause irreversible cytopenias requiring hematopoietic cell support, reduced-intensity (RIC) regimens as those that cause cytopenias of variable duration that may or may not be irreversible, and nonmyeloablative (NMA) regimens as those that lead to minimal cytopenias that will recover without hematopoietic cell support (5). Representative regimens for each intensity level are shown in Table 38-2.
Table 38-2 CONDITIONING REGIMENS
RIC or NMA conditioning may be more appropriate for an older patient with a malignancy sensitive to a GVT effect, such as an indolent non-Hodgkin lymphoma. However, with less-potent conditioning, the benefit of decreased nonrelapse mortality may be negated by an increased risk of relapse. Reduced-intensity conditioning may be an inferior approach for younger patients with more aggressive hematologic malignancies such as AML. The presence of a GVT effect, upon which NMA and RIC conditioning regimens rely, has been indirectly demonstrated in specific disease settings in the form of higher rates of relapse observed when progenitor cells are received from an HLA-identical twin sibling, lower rates of relapse seen in the presence of GVHD, induction of remission by abrupt withdrawal of immunosuppression and directly observed when remission is reestablished after infusion of donor leukocytes in the setting of relapse (6). A schematic representing the relative role of GVT against various malignancies and the relative potencies of various conditioning regimens is provided in Figure 38-1. No recommendation for pairing of any disease entity with a specific conditioning regimen is implied, but RIC and NMA regimens are now increasingly employed in older patients whose diseases are more sensitive to GVT. While in some disease settings conditioning regimens of differing intensities have yielded similar overall survival, prospective trials are ongoing to define the disease and age subgroups that will benefit most from a particular conditioning regimen.
Figure 38-1 Intensities of graft-versus-tumor effect and conditioning regimens.
• Peripheral blood versus bone marrow-derived stem cells: A multicenter prospective study concluded that for patients undergoing myeloablative matched unrelated donor HCT, the use of PB-derived donor stem cells was associated with an increased incidence of chronic GVHD and no improvement in overall survival when compared to the use of BM-derived stem cells. In a separate study, PB-derived stem cells conferred a survival advantage for HCT with matched related donors. How this information will impact the clinical choice of a stem cell source for an individual patient is as yet unclear but the majority of allogeneic stem cells used in transplantation are currently harvested from peripheral blood (7).
• Alternative stem cell sources: The use of HLA-mismatched unrelated donors, umbilical cord blood units, and haploidentical sibling donors has greatly expanded the application of HCT and enabled recipients from ethnic populations not well-represented in international bone marrow donor registries to undergo HCT. Since the first successful umbilical cord transplantation in 1988, single and double umbilical cord transplants have been performed with acceptable rates of GVHD and favorable survival profiles compared to other unrelated donor sources. However, this comes at a cost, both literally in terms of $20,000–$30,000 per cord unit and in terms of slower engraftment, higher rates of infectious complications, and lack of availability of donor cells for future immune manipulation.
Transplants from haploidentical-related donors are also becoming more prevalent and offer the option of subsequent donor lymphocyte infusions if indicated. Haploidentical HCT has historically been complicated by higher rates of GVHD and transplant-related mortality requiring aggressive T-cell depletion and immunosuppressive strategies, which potentially compromise any increased GVT effect created by the recipient-donor HLA disparity. However, innovative approaches employing intensified immunosuppression (e.g., posttransplant high-dose cyclophosphamide) have resulted in survival outcomes comparable to those of other alternative donor sources (8). At this point, how to choose among these alternative sources for patients without fully-matched donors is not clear, but retrospective analyses as well as prospective studies are ongoing to better define optimal donor sources for HCT (9).
AUTOLOGOUS HCT
INDICATIONS
The principal indications for autologous HCT are chemotherapy-sensitive hematologic malignancies for which other therapies have proven unsuccessful. Prospective randomized trials have demonstrated disease- (or event-) free survival and/or overall survival advantages for several hematologic malignancies including: (1) recurrent chemotherapy-sensitive aggressive non-Hodgkin lymphoma, (2) recurrent chemotherapy-sensitive indolent non-Hodgkin lymphoma, (3) recurrent Hodgkin lymphoma, and (4) multiple myeloma (Table 38-1). Emerging indications for patients in first remission include mantle cell lymphoma, peripheral T-cell lymphoma, and primary CNS lymphoma; the timing of autologous HCT for multiple myeloma in the era of modern therapies is an active area of investigation. Autologous HCT has also been performed in patients with treatment-refractory autoimmune diseases. Durable remissions have been achieved in patients with systemic lupus erythematosis, scleroderma, multiple sclerosis, and idiopathic thrombocytopenic purpura.
TOXICITIES
The risks of high-dose chemotherapy followed by autologous HCT include early toxicities of chemotherapy (e.g., gastrointestinal toxicities, oropharyngeal mucositis, severe pancytopenia with risk of infection and/or hemorrhage, and organ injury such as interstitial pneumonitis and hepatic veno-occlusive disease [VOD]) and late toxicities (particularly secondary malignancies, such as myelodysplastic syndrome or AML, after prior use of alkylating agents). Early (before day 100 post-HCT) mortality after autologous SCT is now <5%. Depending on the underlying disease and the conditioning regimen, late secondary hematologic malignancy risk may be as high as 5%–10%. The specific patterns of toxicity and the pharmacokinetics vary with each high-dose chemotherapy regimen.
OUTCOMES
The outcomes of autologous HCT are variable and depend upon the nature and the remission status of the underlying disease. For example, a 3-year disease-free survival probability of approximately 40% has been achieved following autologous HCT for recurrent chemotherapy-sensitive diffuse large B-cell lymphoma (DLBCL) versus 80% for grade III follicular lymphoma. The primary reason for treatment failure is recurrent lymphoma, which occurs in >50% of patients with aggressive NHL after HCT. An active area of investigation within NHL is which subgroups of lymphoma might benefit from HCT in first remission versus the relapsed setting. In multiple myeloma, autologous HCT is pursued not for cure but rather to prolong time without symptoms and progression-free and, possibly, overall survival; in this setting, 3-year survival rates are greater than 70% (10).
ALLOGENEIC HCT
INDICATIONS
Indications for allogeneic HCT include a variety of congenital disorders (e.g., sickle cell anemia), acquired life-threatening hematopoietic stem cell diseases (e.g., severe aplastic anemia), and a wide variety of malignant diseases (Table 38-1). The majority of allogeneic transplants in adults are performed for AML, MDS, and ALL. Advances in our understanding of the diverse molecular underpinnings of each of these diseases have led to improved risk stratification and decision making as to which patients will benefit from transplantation. At present, allogeneic HCT is recommended or considered for all patients with AML except for those who exhibit core binding factor mutations (i.e., inv(16) or t(8:21)), those with normal cytogenetics carrying a mutated NPM1 and wild-type FLT 3, and possibly those with CEBPa mutations (11). Allogeneic HCT is considered even for older patients given the availability of RIC regimens.
TOXICITIES
The early toxicities of myeloablative allogeneic HCT are similar to those of autologous HCT but there is a considerably higher mortality risk, even in the reduced-intensity setting. Selected conditioning regimens are shown in Table 38-2, with use of fludarabine and busulfan-containing regimens in the allogeneic setting increasing in recent years. Some notable complications of any HCT, but particularly of allogeneic HCT, include liver, pulmonary, and renal toxicity. Hepatic VOD is a syndrome characterized by the constellation of weight gain, ascites, right upper quadrant pain, and liver dysfunction often leading to subsequent renal or multiorgan system failure. Data have suggested that defibrotide administration can improve the survival rate in severe VOD from less than 20% to over 40% if started soon after diagnosis (12). Pulmonary complications include diffuse alveolar haemorrhage which usually occurs within 30 days of transplant and idiopathic pneumonia syndrome which typically presents later. Both are treated with high-dose glucocorticoids and potentially anti-TNF agents (e.g., etanercept), but both carry high mortality rates despite aggressive therapy (13). A feared complication that may manifest early or late is thrombotic microangiopathy and nephropathy, which reflects endothelial injury provoked by multiple agents including chemotherapies, infection, GVHD, radiation, and calcineurin inhibitors (14). Care is usually supportive and involves minimizing exacerbating medications and further insults.
OUTCOMES
The outcomes of allogeneic HCT vary widely by disease status, conditioning regimen, age, comorbidities, and severity of subsequent GVHD. Probabilities of 3-year overall survival can range from 76% after an MRD transplantation for CML in chronic phase to 19% in Philadelphia chromosome-positive ALL not in remission at the time of an MRD transplant (1).
GRAFT-VERSUS-HOST DISEASE
One of the most challenging and actively investigated sequelae of allogeneic HCT is graft-versus-host disease (GVHD). Patients with acute and especially chronic GVHD have a lower probability of relapse of their underlying malignancy. In some hematologic malignancies, this reduction in relapse probability has translated into an overall survival advantage (e.g., most advanced acute leukemias), especially when GVHD is present to a moderate degree. In other settings, the mortality risk of the GVHD has negated any beneficial antitumor effect and has not conferred a survival advantage after allogeneic transplantation (e.g., “good risk” AML in first remission). (For full discussion of the pathophysiology of and therapies for GVHD, see Chapter 37.)
ACUTE GVHD
The risk of an allogeneic HCT recipient developing some degree of acute GVHD ranges from 20% to 80%, depending on histocompatability of the donor and recipient and the GVHD prophylaxis strategy used (15). Acute GVHD is a multiorgan system disease initiated by immunocompetent T cells in the donor graft. The primary targets involved by acute GVHD are the skin (rash), gastrointestinal tract (nausea, vomiting, diarrhea), and liver (jaundice, enzyme elevation).
CHRONIC GVHD
Chronic GVHD, which typically presents several months after HCT, occurs in 40%–80% of patients and is manifested by a wider spectrum of organ involvement. Chronic GVHD mimics many classic autoimmune disorders with, for example, sclerodermatous skin changes, a Sjögren’s disease-like sicca complex, esophageal dysmotility, and cholestatic hepatopathy. An acute/chronic GVHD overlap syndrome has also been described and is associated with a worse prognosis as compared to chronic GVHD (15). The prognosis of GVHD is related to its stage, which is dependent upon the severity of individual organ involvement, and response to treatment.
TREATMENT
GVHD may be effectively prevented by in vivo or ex vivo depletion of T cells from the donor graft. T-cell depletion of a graft, however, is complicated by a higher rate of engraftment failure and a higher risk of relapse (owing to the loss of a GVT effect). An arsenal of immunosuppressive drugs is available to manage GVHD, with calcineurin inhibitor-based combinations being the basis of pharmacoprophylaxis and glucocor-ticoids being the first-line therapy for both acute and chronic GVHD (Table 38-3). While management of grades I–II acute GVHD is usually successful, more advanced (grades III–IV) GVHD is more difficult to manage, with mortality rates of greater than 50%. Reasons for treatment failure and mortality secondary to GVHD are myriad but opportunistic infections are prominent.
Table 38-3 GVHD-RELATED THERAPIES
INFECTIOUS COMPLICATIONS AND MONITORING
Many of the advances in HCT over the past three decades have been the result of better prevention of infectious complications and prevention and treatment of GVHD. Anti-infective prophylaxis is now routinely employed given the severely immune compromised state of the peritransplant period and the continued impairment of cellular and humoral immunity which lasts for months to years after transplantation. Guidelines established by the CDC/ASBMT/IDSA recommend (16):
• Quinolone prophylaxis for neutropenia expected to last 7 days or more.
• Antifungal prophylaxis with fluconazole or micafungin preengraftment; prophylaxis with voriconazole or posaconazole after engraftment, particularly in the setting of GVHD.
• Antiviral (CMV, HSV, VZV) prophylaxis with acyclovir or equivalent antiviral therapy.
• Anti-Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole.
Newer generation broad-spectrum antibiotics, new antiviral agents, and anti-fungal agents with reduced toxicity and a broader spectrum of coverage are available for patients with suspected or established opportunistic infections.
Cytomegalovirus (CMV), one of the chief infectious causes of mortality in the early allogeneic HCT experience, may be prevented by donor selection (CMV-seronegative donors for CMV-seronegative recipients whenever possible), the routine monitoring for CMV reactivation posttransplant (by PCR-based or antigenemia assays), and the preemptive use of ganciclovir for patients with demonstrated viremia. With the more widespread use of umbilical cord blood donors, an increased incidence of viral infections has been observed (accounting for 30% of deaths), particularly infections with BK virus, EBV and resulting lymphoproliferative diseases, adenovirus, and HHV-6. Neurologic manifestations of HHV-6 have been reported and routine monitoring for EBV and HHV-6 in addition to CMV is advised in UCB settings (17) (Figure 38-2).
FIGURE 38-2 Immune defenses and susceptibility to infection post HCT. EBV, Epstein-Barr virus; HHV, human herpesvirus 6; NK, natural killer; PTLD, posttransplant lymphoproliferative disease. (From Mackall C, Fry T, Gress R, et al. Background to hematopoietic cell transplantation, including posttransplant immune recovery. Bone Marrow Transplantation. 2009; 44: 457–462.)
Other important supportive care measures include red blood cell and platelet transfusional support. Blood products are irradiated to prevent transfusion-associated GVHD, and third-generation leukocyte reduction filters are used to prevent allosensitization, febrile nonhemolytic transfusion reactions, and CMV transmission. Total parenteral nutrition is often required because of poor oral nutrition resulting from oropharyngeal mucositis and frequent nausea and vomiting.
FUTURE DIRECTIONS
Hematopoietic HCT has become more widely applicable in large part secondary to the expansion of donor sources (i.e., matched or mismatched unrelated donors, haploidentical donors, and umbilical cord blood) and the expansion of eligibility criteria to include many patients who were previously believed to be too old or too ill to have a transplant (i.e., through RIC or NMA conditioning, improved supportive care, etc.). Further improvement in the outcomes of HCT may stem from the approaches listed below:
• Disease-specific: More effective eradication of the underlying disease, via targeted or maintenance therapies (e.g., FLT 3-inhibitors, lenalidomide, radiolabeled antibodies, adoptive therapy using chimeric T-cell receptors) and targeting of the malignant, noncycling stem cell.
• Patient selection: Improvement in identifying those patients at less risk for relapse in whom transplant-related mortality can be avoided by choosing less-intensive conditioning.
• Regimen selection: Clarification of disease and patient populations for whom specific conditioning and stem cell combinations yield the greatest overall survival.
• Engraftment/immune reconstitution: Especially for umbilical cord transplants, enhanced immune reconstitution by ex vivo or in vivo expansion or by better selection of units.
• Separation of GVT from GVHD: Manipulation of the initial immunologic platform via adoptive immunotherapy to: (1) enhance reactivity to tumor antigens (e.g., via NK- or T-cell or DC subset manipulation) and (2) decrease global alloreactivity (e.g., via depletion of alloreactive T-cell subsets, augmenting regulatory T-cell populations, or insertion of suicide gene cassettes) (18, 19).
Our understanding of the biology of malignant stem cells and characterization of the immune cells involved in GVT and GVHD are continually improving in concert with early-phase clinical trials introducing new classes of agents into the transplant arena (20). Advances in relapse-free and overall survival outcomes following HCT are expected to result from these emerging and promising therapies.
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