Table 23-3 lists the complications associated with HCT; the most common are discussed below. The first 100 days following transplantation are the time of greatest risk for recipients of autologous and allogeneic HCT. Care by physicians skilled in the management of patients undergoing these procedures is of critical importance.
Table 23–3.Complications of Hematopoietic Cell Transplantation ||Download (.pdf) Table 23–3. Complications of Hematopoietic Cell Transplantation
Vascular access complications
Blood group incompatibilities and hemolytic complications
Herpes simplex virus infections
Varicella-zoster virus infections
Epstein-Barr virus infections
Adenovirus, respiratory viruses, HHV-6, -7, -8, and other viruses
Sinusoidal obstructive syndrome
Hepatitis: infectious versus noninfectious
Interstitial pneumonitis: infectious versus noninfectious
Diffuse alveolar hemorrhage
Kidney and bladder complications
Growth and development
Late onset nonmalignant complications
Osteoporosis/osteopenia, avascular necrosis, dental problems, cataracts, chronic fatigue, psychosocial effects, and rehabilitation
Infectious, transplant conditioning and immune suppression medication toxicities
Graft failure is defined as the lack of donor hematopoietic cell engraftment following autologous and allogeneic HCT. Criteria are predominantly operational, and graft failure is divided into primary (early) and secondary (late) phases. The consequences of graft failure are significant, and include high risks of death from infection, hemorrhage, or relapsed malignancy.
Primary (Early) and Secondary (Late) Graft Failure
Myeloid engraftment has commonly been defined as the first of three consecutive days on which the absolute neutrophil count exceeds 5 × 108/L. Myeloid engraftment typically occurs within 21 days of the graft infusion, irrespective of graft source. Platelet recovery is more variably defined, often as the first day of a platelet count of at least 20, 50, or 100 × 109/L, sustained without transfusion for 7 days. Platelet recovery may be substantially delayed compared with myeloid recovery, particularly with lower CD34+ cell doses or UCB allografts. A hemoglobin level of at least 8 g/dL without transfusion support is an accepted threshold for red cell engraftment. These criteria were derived from the predictable kinetics seen after myeloablative conditioning. With RIC, many patients never develop severe cytopenias, and thus engraftment in these settings is usually defined, at least in part, by assessment of donor chimerism in the blood or marrow. In these settings, graft loss is typically defined by donor chimerism of less than 5 percent in blood CD3+ cells.
Primary graft failure is defined as failure to achieve these threshold counts or donor chimerism levels at any point beyond day +28. Isolated cytopenias does not necessarily herald graft failure, as they may be transitory phenomena related to infection, medications, lineage-specific immune-mediated cytopenias, or GVHD. Secondary (late) graft failure occurs in patients who initially meet criteria for engraftment but subsequently lose graft function in at least two cell lines. Late graft failure is more often associated with allogeneic HCT than with autologous transplantation; possible causes include graft rejection related to residual host immunity, persistent or progressive malignancy, low donor cell yield, medication side effects, infection, or GVHD.
Graft Rejection and Poor Graft Function
Graft rejection is a subset of primary or secondary graft failure caused by immune-mediated rejection of donor cells by residual host effector cells. A diagnosis of graft rejection requires analysis of blood or marrow for donor hematopoietic chimerism; graft rejection is defined as the inability to detect a meaningful percentage (usually >5 percent) of donor hematopoietic elements. In contrast, poor graft function describes the failure to achieve adequate blood counts following allogeneic HCT in the presence of substantive donor hematopoietic cell chimerism.
Graft Failure Following Reduced-Intensity Conditioning
Allogeneic HCT following RIC is associated with incomplete eradication of host hematopoiesis. As a consequence, a significant percentage of patients have mixed donor/host hematopoietic chimerism for several months after transplantation before converting to complete donor type.186,293 Primary engraftment following reduced-intensity allogeneic HCT is defined by neutrophil, platelet, and hemoglobin count recovery as outlined above as well as stable donor T-cell chimerism. As described above, graft failure is said to have occurred when blood donor T-cell chimerism is less than 5 percent at any point after reduced-intensity allogeneic HCT. Donor T-cell chimerism levels greater than 5 percent but less than 95 percent are generally termed “mixed chimerism,” while full donor chimerism is defined by blood donor T-cell chimerism of 95 percent or greater.
Incidence of Graft Failure
The incidence of graft failure varies widely in published reports. To estimate the incidence of graft failure following autologous HCT, consider that in most centers the TRM associated with autologous HCT is less than 5 percent, of which only a small subset can be attributed to graft failure. Another surrogate marker for estimating the incidence of graft failure following autologous HCT is the requirement for hematopoietic cell rescue using a backup autograft product. A study of 300 patients who underwent autologous HCT revealed that 4.7 percent required their backup product.294 Thus, it is reasonable to estimate that the incidence of graft failure following autologous HCT is somewhere between 1 and 5 percent.
Graft failure following allogeneic HCT is more complex, because of confounding factors such as histocompatibility, ABO matching, graft-versus-host and host-versus-graft reactions, and the use of postgrafting immunosuppression. The overall incidence of graft failure after allogeneic HCT is approximately 5 to 6 percent.295 In general, graft failure is uncommon after high-dose conditioning and in patients who are heavily pretreated with cytotoxic chemotherapy before coming to allogeneic HCT. Even in the myeloablative setting, though, the incidence of graft failure varies with conditioning regimen, as illustrated in a randomized trial where graft failure occurred in zero of 64 (0 percent) of patients receiving BU/CY but in five of 62 (8 percent) of patients receiving BU/FLU.174 The risk of graft rejection is highest in patients who are heavily presensitized or who have autoimmunity directed at hematopoietic cells (as in aplastic anemia), those who receive low CD34+ cell doses,295,296 and those with diseases such as myelofibrosis where the marrow microenvironment is significantly perturbed.
The consequences of graft failure, and its optimal treatment, depend in large part upon the likelihood of autologous hematopoietic recovery. In patients who have received high-dose conditioning, autologous marrow recovery is likely to be severely delayed if not absent, and graft failure is associated with high mortality rates as a consequence of prolonged cytopenias. Second-salvage allogeneic HCT has been used successfully to treat graft failure in this setting; reported outcomes vary from dismal to encouraging,297,298 and likely depend substantially on patient selection. There is no consensus on whether to use the same or a different donor for salvage allogeneic HCT for graft rejection, and the decision often depends on donor availability. The time needed to identify and collect a second allograft product are often prohibitive for patients with graft rejection and pancytopenia, and thus readily available HSC sources such as UCB and HLA-haploidentical family members have sometimes been used.
For patients with graft failure after RIC, autologous hematopoietic recovery is more likely. For these patients, the optimal strategy often involves withdrawing postgrafting immunosuppression and awaiting autologous count recovery. However, for patients with malignant disease, the risk of relapse is substantially elevated in the setting of graft failure,295 presumably as a result of a loss of GVT effects.
REGIMEN-RELATED ORGAN TOXICITIES
The severity of organ toxicities associated with HCT is a function of the intensity of conditioning therapy, the amount of prior therapy received, patient comorbidities before transplantation, and posttransplantation factors such as immunosuppressive medication and antimicrobial agents.
Mucositis occurs in more than 90 percent of patients receiving high-dose regimens and is often regarded as the most difficult issue from the patient’s perspective.299 Current management is supportive and includes frequent rinsing with saline solutions and antimicrobials, cryotherapy, pain control (often with continuous intravenous infusions of opioids), and parenteral nutrition when needed. Improvement typically occurs within 10 to 21 days of transplantation, around the time of engraftment. Fully ablative regimens, TBI-based conditioning, and the administration of posttransplantation methotrexate (MTX) for GVHD prevention are associated with more severe mucositis.300 Severe mucositis may result in significant tissue edema, upper airway obstruction, and/or aspiration pneumonitis, although fortunately these complications are rare. Regimen-related gastroenteritis results in nausea, vomiting, and diarrhea, which may persist for weeks after the transplant. Breaches in the mucosal lining predispose to bacterial translocation from the gastrointestinal tract, with increased risk of bacteremia and sepsis. Palifermin (keratinocyte growth factor) can reduce patient-controlled anesthesia (PCA) and total parenteral nutrition (TPN) usage because of mucositis, predominantly in patients receiving TBI-based conditioning,301 but at a cost of $5500 to $14,000 per day.302 Initial hopes that this agent would prevent GVHD after allogeneic HCT have not been realized,303,304 and the benefits of palifermin appear limited to ameliorating mucositis.
Sinusoidal Obstructive Syndrome
Sinusoidal obstructive syndrome (SOS) is a clinical syndrome of regimen-related hepatotoxicity characterized by tender hepatomegaly, fluid retention, weight gain, and elevated serum bilirubin following autologous or allogeneic HCT. This syndrome was formerly called venoocclusive disease (VOD), but this term is no longer used as it inaccurately describes the underlying pathobiology: the liver injury is initiated by damage to hepatic sinusoidal epithelium, and obstruction of hepatic venules is not essential to the development of the syndrome.305 The incidence of SOS varies significantly with the intensity of conditioning and with the stringency of diagnostic criteria, from less than 10 percent to as high as 30 to 40 percent. CY is a key culprit in the development of SOS, and large interpatient variability in CY metabolism may account for the syndrome’s unpredictability.306,307 Other contributing factors include the preadministration of BU in the BU/CY regimen, which potentiates CY hepatotoxicity172; preexisting hepatic fibrosis, as in patients with cirrhosis or with hepatic extramedullary hematopoiesis as in myelofibrosis308; and pretreatment with higher doses of gemtuzumab ozogamicin.309,310 The incidence of SOS appears to be decreasing over time,311 likely a result of the prevalence of RIC regimens and the prophylactic use of ursodiol, which prevents SOS and other forms of hepatic injury during allogeneic HCT.312,313
SOS is generally is classified as mild (clinically apparent yet resolves without treatment), moderate (requiring diuretics and pain medication for abdominal discomfort yet completely resolves before day +100), or severe (not resolving before day +100 or death).314 Severe SOS has a tendency to progress to multiorgan failure and is associated with a mortality rate of greater than 80 percent.315 Therapy for SOS is supportive and includes management of sodium and water balance with diuretics, preservation of renal blood flow, and paracentesis for ascites associated with significant discomfort or pulmonary compromise. Patients with a poor prognosis can be recognized early after SOS onset by steep rises in serum bilirubin, body weight, and other liver enzymes; hepatic venous pressure measurement greater than 20 torr; development of portal vein thrombosis; and multiorgan failure requiring mechanical ventilation or renal dialysis.316
There are few satisfactory therapies for severe SOS; the most commonly used is intravenous defibrotide, a mixture of single-stranded porcine oligodeoxyribonucleotides which induces antithrombotic and fibrinolytic effects in preclinical models.317 Its mechanism of action against SOS remains unknown. A randomized phase II dose-finding trial involving 149 patients with severe SOS reported day +100 survival of 42 percent with few adverse events, and a dose of 25 mg/kg/day was selected for ongoing randomized phase III trials.318 However, defibrotide is not yet approved by the FDA and remains available only on an investigational or compassionate-use basis in the United States.
Noncardiogenic and noninfectious diffuse lung injury, also referred to as idiopathic pneumonia syndrome (IPS), remains a significant problem following autologous or allogeneic HCT, occurring in 10 to 15 percent of transplant recipients.319 Risk factors for idiopathic IPS include high-dose conditioning, TBI, GVHD, older recipient age, prior history of cigarette smoking, prior thoracic/mediastinal irradiation, and abnormal gas exchange as measured by pretransplant pulmonary function testing.320 Preclinical models suggest that donor T cells play a key role in the development of IPS, indicating that it may be a form of graft-versus-host reaction.319 In a small subset of patients, diffuse alveolar hemorrhage (DAH) develops, characterized by progressive shortness of breath, cough, and hypoxemia. Classically, DAH is defined by the demonstration of progressively bloodier aliquots in bronchoalveolar lavage fluid. Mortality from this complication is high (often >75 percent) despite aggressive treatment. Another subset of patients with IPS develop periengraftment respiratory distress without a bloody bronchoalveolar lavage. In the autologous setting, the IPS often responds promptly to glucocorticoids, whereas in the allogeneic setting response rates are lower, indicating that perhaps some cases may be complicated by GVHD.
The management of suspected IPS begins with bronchoscopy to rule out infectious etiologies and to evaluate for DAH. Care is supportive and aimed at maximizing respiratory function and preventing volume overload or multiorgan failure. Patients are typically treated with high-dose glucocorticoids (methylprednisolone at 2 mg/kg/day or higher), along with broad-spectrum antimicrobials and intensive supportive care. Retrospective studies have suggested that tumor necrosis factor (TNF) blockade with etanercept may be effective as an adjunct to high-dose glucocorticoids,321 but a prospective randomized study failed to find an additive benefit,322 and thus etanercept cannot be routinely recommended at this time. Patients with IPS who progress to require mechanical ventilation have a very poor prognosis, and a frank discussion of the goals of care is indicated in this setting, particularly in the presence of multiorgan failure.323
Lung inflammation following the administration of BCNU is a separate form of noninfectious lung injury seen in HCT recipients who receive this agent as part of their conditioning regimens. BCNU-induced pneumonitis is often characterized by a nonproductive cough with increasing dyspnea and bilateral pulmonary infiltrates on chest radiography, with or without fevers, and often occurs 1 to 2 months after transplantation.324 Pulmonary function tests reveal a restrictive pattern of lung injury and a decrease in diffusing capacity compared to pretransplant values. Prompt treatment with glucocorticoids reduces mortality and morbidity and is crucial to a successful outcome. If untreated or recognized late, significant pulmonary fibrosis may develop.
Susceptibility to infection is a significant challenge in the clinical management of transplant recipients. The essential principles are prevention, judicious monitoring, and expeditious treatment of all bacterial, fungal, and viral infections. These basic principles are widely accepted, yet the day-to-day strategy for implementing them varies widely among transplant physicians and centers. Two universally important measures for reducing infections in immunocompromised transplant recipients are effective handwashing policies and a strategy for preventing transmission of respiratory viruses, including metapneumovirus, respiratory syncytial virus, parainfluenza, and influenza.
The duration of neutropenia and severity of oral and gastrointestinal mucosal damage from the conditioning regimen are risk factors for infection before neutrophil recovery has occurred. Following neutrophil recovery, deficiencies of B- and T-cell–mediated immunity persist and increase susceptibility to opportunistic infections. Immune recovery following autologous HCT is relatively rapid compared to after allogeneic transplantation. Most autologous transplant recipients recover T-cell immunity specific for herpes viruses, including CMV, by 3 months after transplantation.325 The degree and duration of immunodeficiency following allogeneic HCT are influenced, in part, by the type of immunosuppressive therapy and severity of GVHD. Chronic GVHD is associated with chronic B- and T-cell immune deficiencies that may persist for years, and Ig production and reticuloendothelial function may also be impaired.326,327,328
Bacterial infections are common during the period of immediate neutropenia that follows the preparative transplantation regimen, and can be caused by both Gram-positive and Gram-negative organisms.329 The increased risk of bacterial infections is not only caused by neutropenia, but also from loss of epithelial integrity from regimen-related injury, bacterial translocation, and the presence of indwelling intravenous catheters. Some centers institute preventive measures in addition to rigorous hand washing, such as gowning and masking, although there is little evidence that these actions reduce infection risk. Removal of venous catheters is sometimes required for patients who do not respond promptly to treatment. Chapter 24 reviews specific strategies and regimens for treating bacterial infections in neutropenic patients.
Patients who require ongoing immunosuppressive therapy for the control of chronic GVHD are at risk for recurrent bacteremia with encapsulated bacteria and sinopulmonary infections. Preventive strategies differ from institution to institution, although some form of antibiotic prophylaxis is often used in these patients. Infrequent bacterial pathogens which should also be considered, especially in the presence of pulmonary infiltrates or nodules, are Legionella, Nocardia, Mycobacterium tuberculosis, and atypical mycobacteria.
Fungal infections are serious and potentially fatal complications following HCT, and are seen most commonly in allogeneic HCT recipients as a result of the requirement for postgrafting immunosuppressive medication. The incidence of fungal infection varies considerably among transplantation centers because of a variety of factors, including geographic location, nearby construction, and prophylactic regimens. Candida and Aspergillus are the most common fungal pathogens; however, other organisms can also cause life-threatening infections. Chapter 24 discusses the treatment and prophylaxis of fungal infections.
Fluconazole prophylaxis decreases the incidence of invasive and superficial Candida albicans infections and may decrease the 100-day mortality in allogeneic HCT recipients.330 Fluconazole has limited activity against Candida krusei, Torulopsis glabrata, and Aspergillus species, and some centers reported an increased incidence of resistant Candida infections in patients receiving prophylactic fluconazole.331 More aggressive prophylaxis with mold-active agents such as voriconazole or itraconazole can prevent invasive mold infections, including aspergillosis, but these agents are associated with a higher risk of adverse events and no clear benefit to mortality.332,333
Infection with herpesviruses can cause significant morbidity and mortality in HCT recipients. Most infections are a result of viral reactivation and follow a relatively predictable temporal pattern in the absence of prophylaxis: Herpes simplex virus (HSV) causes clinically apparent disease at approximately 2 to 3 weeks after HCT, CMV disease usually occurs during the second to third month, and varicella-zoster virus (VZV) recurrences present at a median of 5 months after HCT.334
CMV is an important viral pathogen in HCT recipients. Infection occurs from reactivation of latent virus or is newly acquired from the donor graft or blood transfusions. Reactivation is a common problem in allogeneic HCT, but is relatively rare after autologous HCT except in the setting of CD34+ selection and T-cell depletion.123 Before effective prevention strategies were introduced, CMV infection developed in 70 percent of CMV-seropositive transplant recipients and 32 percent of CMV-seronegative recipients and was a frequent cause of TRM.335 Currently, all allogeneic HCT recipients at risk for CMV infection (those who are CMV-seropositive or who have a CMV-seropositive donor) require monitoring with preemptive therapy for CMV reactivation; this approach has markedly reduced the risk of progression to frank CMV disease such as enteritis or pneumonitis.336 Prophylactic antiviral therapy against CMV is used by some centers, particularly in high-risk situations such as UCB recipients. More commonly, allogeneic HCT recipients are monitored with plasma CMV polymerase chain reaction (PCR) assays at least weekly through at least day +100 after HCT, and are treated preemptively if these studies yield values which exceed institutionally established thresholds.334 The preemptive approach avoids the toxicity of universal antiviral prophylaxis, reduces the risk of acquired antiviral resistance, and limits overtreatment of CMV while preventing development of tissue disease. However, CMV tissue disease such as enteritis or pneumonitis can, rarely, develop despite negative plasma CMV PCR, and CMV enteritis or pneumonitis cannot be definitively ruled out by blood tests alone.
Prophylaxis with acyclovir or, more potently, valacyclovir can reduce the risk of CMV reactivation after allogeneic HCT, but does not obviate the need for CMV surveillance.337,338 Intravenous ganciclovir is typically the first-line treatment for CMV reactivation or tissue disease, although oral valganciclovir may be equally effective as preemptive therapy.339,340 The most common adverse effect of these antiviral drugs is myelosuppression, which often requires growth-factor support. Intravenous foscarnet is as effective as ganciclovir in CMV prevention and treatment,341 and does not cause myelosuppression. However, foscarnet is nephrotoxic and requires cumbersome pre- and posthydration, and is thus most often used as second-line therapy in patients who cannot tolerate ganciclovir because of myelosuppression. Patients with CMV reactivation are typically treated with an induction dose of anti-CMV therapy (ganciclovir, valganciclovir, or foscarnet) for at least 2 weeks, followed by maintenance antiviral therapy until CMV assays are persistently negative. It is not uncommon for patients to experience additional late reactivations after antiviral therapy is discontinued, and these patients require ongoing monitoring beyond day +100.
Investigational approaches to CMV prevention and treatment include CMX-001, an oral prodrug that is converted to cidofovir intracellularly and lacks renal toxicity. A placebo-controlled randomized trial of CMX-001 as CMV prophylaxis in allogeneic HCT found that this agent reduced the incidence of CMV activation from 37 percent to 10 percent.342 Diarrhea was the most common adverse effect; myelosuppression and nephrotoxicity were not observed. Letermovir, a novel terminase inhibitor, has also shown efficacy in preventing CMV reactivation in allogeneic HCT in randomized, placebo-controlled clinical trials.343 Maribavir, another antiviral agent with a novel mechanism of action, was effective in preventing CMV in a randomized dose-finding study,344 but failed to demonstrate a benefit in a randomized phase III clinical trial.345 Donor-derived CMV-specific cytotoxic lymphocytes have also been used investigationally with some success.346
HSV and VZV are two other members of the herpesvirus family that cause significant morbidity in the posttransplantation setting. These viruses share the characteristics of latency, reactivation, and neurotropism. Virtually all HSV disease occurring after HCT is a result of reactivation, and the serologic status of the transplant recipient determines the risk for disease and the requirement for prophylaxis. Oral mucositis, cutaneous infections, esophagitis, genital herpes, and pneumonia are the most common clinical manifestations. Acyclovir is highly effective for the prevention and treatment of HSV and should be administered to all HSV-seropositive transplant recipients, beginning before or during conditioning. Acyclovir prophylaxis is often continued for at least 1 year after HCT (or longer if patients remain on immunosuppressive therapy), as this approach reduces the risk of late HSV recurrence.347 Acyclovir is well tolerated immediately after transplantation with no effect on the recovery of neutrophil counts. Valacyclovir is an acceptable alternative. Patients do not require concomitant acyclovir prophylaxis while receiving maribavir, foscarnet, valganciclovir, ganciclovir, or cidofovir for treatment of another virus, because these agents have adequate anti-HSV activity. Acyclovir resistance is rare in HSV and can be treated using foscarnet.348
Recurrent VZV disease can occur after both allogeneic and autologous HCT. The initial manifestations of recurrence are localized in approximately half of patients. Treatment with acyclovir within 24 to 48 hours of the onset of herpes zoster prevents dissemination and shortens the course of cutaneous disease. The failure of VZV infections to resolve quickly or their recurrence shortly after acyclovir therapy is discontinued is usually a function of the limited host immune response and is generally not a result of acyclovir resistance. For the rare cases of acyclovir-resistant VZV, foscarnet is the most commonly used alternate therapy.348 Acyclovir, given for at least 1 year after HCT, is highly effective in preventing VZV recurrence.349 Pilot studies of vaccination with live attenuated VZV in allogeneic HCT recipients suggest that this approach is safe and effective in selected patients (median of 4 years posttransplantation, off systemic immunosuppression, blood CD4+ cell count >200/μL),350 but larger studies are required before vaccination can be widely recommended. Heat-inactivated VZV vaccination has also been reported as efficacious in recipients of autologous HCT.351
ACUTE GRAFT-VERSUS-HOST DISEASE
Acute GVHD remains one of the most serious and challenging complications of allogeneic HCT. The requirements for the development of acute GVHD were described more than 40 years ago: the graft must contain immunologically competent cells, the recipient must express tissue antigens not found in the donor, and the recipient must be immunologically suppressed such that an effective response against transplanted cells cannot occur.352 HLA disparities are potent triggers of GVHD, but in the setting of HLA-matched donor/recipient pairs GVHD is mediated by minor histocompatibility antigen disparities which provoke a donor T-cell response.353,354 There are two primary classes of MHC antigens in humans: HLA class I antigens have a broad distribution and are expressed on nearly all cells, whereas HLA class II antigen expression is restricted to macrophages, dendritic cells, B cells, and activated T cells. Minor histocompatibility antigens are endogenous cellular proteins which are subject to significant genetic polymorphism and are presented to donor T cells as small peptides bound in the grooves of the major histocompatibility antigens.355 Some minor histocompatibility antigens associated with GVHD include CD31, HA-1, and the male-specific DBY gene.356,357 There are likely hundreds if not thousands of minor histocompatibility antigens relevant to allogeneic HCT, of which only a handful have been identified to date. Efforts are underway to utilize genome-wide association studies to broaden our knowledge of these determinants of GVT effects and GVHD.358
The most important risk factor for the development of acute GVHD is the degree of HLA disparity between donor and recipient. The increased incidence of acute GVHD with fully HLA-matched unrelated donors compared to HLA-identical sibling donors is likely related to increased disparity in minor histocompatibility antigens or unrecognized disparities in the phenotypically matched major histocompatibility loci.359 Other risk factors for acute GVHD development include conditioning intensity, use of TBI, and possibly graft source (although the effect of graft source on acute GVHD incidence is not consistently observed).72,359
Classically, acute GVHD was defined temporally by its occurrence before day +100 after allogeneic HCT. With RIC, acute GVHD can occur beyond day +100, and the distinction between acute and chronic GVHD is now based on organ involvement and histology rather than time of onset.360 Acute GVHD affects the skin, gastrointestinal (GI) tract, and liver (although liver involvement is increasingly rare, for reasons which are not entirely clear).218 The overall incidence of acute GVHD after allogeneic HCT is 40 to 60 percent,359 although the incidence may vary widely in specific settings depending on conditioning regimen, HLA matching, and graft source.
Skin involvement manifests as a rash, which may be localized and maculopapular or diffusely erythematous with bullae and desquamation in very severe cases. Definitive diagnosis requires skin biopsy and interpretation by an experienced pathologist.361 However, skin biopsies are often inconclusive, and the diagnosis is often made on clinical grounds in patients with a skin rash consistent with acute GVHD arising during the appropriate timeframe after allogeneic HCT. Decision analysis supports the concept that the diagnosis of skin GVHD can be made clinically and does not require skin biopsy in patients with a pretest likelihood of acute GVHD of 30 percent or greater (the majority of allogeneic HCT recipients).362
GI manifestations of acute GVHD can affect the upper GI tract (presenting as nausea, emesis, anorexia, and weight loss), the lower GI tract (presenting as diarrhea with or without abdominal cramping and hematochezia), or both. Upper-GI involvement with acute GVHD is likely underdiagnosed, since the symptoms may be mild and posttransplant anorexia and nausea are often nonspecific and multifactorial. Diagnosis requires upper endoscopy and endoscopic biopsy, with interpretation by an experienced pathologist. The diagnosis of upper-GI acute GVHD is clinically important, because this syndrome often responds dramatically to even low-dose treatment and, if left untreated, can cause significant nutritional compromise.
Lower-GI involvement with acute GVHD is a more serious and feared complication of allogeneic HCT. These patients present with substantial diarrhea, often several liters per day, accompanied by pain and bleeding. The diarrhea of acute GVHD is secretory, related to epithelial injury, and typically persists around the clock. Abdominal computed tomography (CT) findings, particularly bowel-wall thickening, are common in acute GVHD,363 but CT findings alone are insufficient for diagnosis. Patients with suspected lower-GI GVHD should undergo endoscopic evaluation and biopsy as soon as feasible, although in the setting of myeloablative conditioning it is often difficult to differentiate regimen-related GI injury from acute GVHD endoscopically or histologically before day +20. Flexible sigmoidoscopy is viewed as a sufficient diagnostic test in most cases,364,365 and is far easier to perform than full colonoscopy as it does not require an aggressive preparatory regimen. Visual inspection of the gut mucosa is often sufficient to advance a diagnosis of acute GVHD and initiate treatment,366 particularly if the endoscopist has experience in evaluating allogeneic HCT recipients, but biopsies remain essential to rule out CMV enteritis and other etiologies.365 Mucosal denudation is a particularly concerning endoscopic finding,366 and is associated with a grim prognosis.
Hepatic GVHD presents with abnormal liver function tests, most commonly elevated bilirubin and alkaline phosphatase. Liver biopsy is required for definitive diagnosis, but is rarely performed because of the low pretest likelihood of hepatic GVHD in the modern era and because of procedural risk. When biopsies are performed, the most common finding associated with hepatic GVHD is bile-duct injury and loss resulting in cholestasis.367 Numerous other etiologies can cause abnormal liver function tests in allogeneic HCT recipients, including SOS, viral hepatitis, regimen-related hepatotoxicity, and medication-related hepatotoxicity (particularly with triazoles and CSP). Hepatic GVHD is relatively uncommon except in the setting of severe multisystem acute GVHD.
The current model of acute GVHD requires three steps. In step 1, the transplantation conditioning regimen damages host tissue, leading to increased secretion of inflammatory cytokines such as TNF-α and IL-1. These cytokines enhance alloreactivity of donor T cells by upregulating the expression of major and minor host tissue histocompatibility antigens and also affect other molecules on host antigen-presenting cells (APCs). Regimen-related damage to the GI tract results in leakage of endotoxins such as lipopolysaccharides into the systemic circulation, where they serve as additional inflammatory stimuli.353 In step 2, resting donor T cells become activated in secondary lymphoid organs by host or donor APCs, which present alloantigens to the T-cell receptor in the context of MHC. Costimulatory signals are required for full T-cell activation. Donor T-cell activation is characterized by cellular proliferation and predominance of Th1 cells and the secretion of IL-2 and IFN-γ. In step 3, cellular effectors mediate tissue injury and destruction in the target organs, resulting in the clinical manifestations of acute GVHD. This step involves the continued release of inflammatory cytokines that direct specific antihost donor-derived T cells to migrate to the target tissues of acute GVHD, namely, skin, liver, and gut. Neutrophils and mononuclear phagocytes contribute to local tissue injury by amplifying the proinflammatory response.
Without some form of GVHD prophylaxis, virtually all patients undergoing allogeneic HCT would develop severe or fatal acute GVHD. Immunosuppressive drugs are the mainstay of acute GVHD prevention, and all patients undergoing allogeneic HCT with a T-cell-replete graft require prophylaxis. On the basis of randomized clinical trials published in the 1980s, the most commonly used regimen in myeloablative allogeneic HCT is the combination of a calcineurin inhibitor (CSP or tacrolimus [TAC]) with a short course of MTX, generally given on days +1, +3, +6, and +11 after allotransplantation.368,369 The addition of prednisone to this backbone paradoxically increased the risk of acute GVHD in a randomized clinical trial, and thus glucocorticoids are rarely used for GVHD prophylaxis.370 Two randomized studies demonstrated that TAC was superior to CSP in preventing acute GVHD after myeloablative allogeneic HCT,371,372 and thus TAC has largely supplanted CSP in this setting. A recent randomized clinical trial conducted by the BMT-CTN compared TAC/sirolimus (TAC/SRL) to the standard TAC/MTX regimen as GVHD prophylaxis after myeloablative allogeneic HCT. The primary endpoint (day +114 survival free of acute GVHD grades II to IV) was not significantly different in the two arms, nor were overall or progression-free survival.300 The toxicity profiles of the two regimens differed somewhat, but did not impact TRM. Interestingly, there was a strong trend toward a higher incidence of chronic GVHD in the SRL-containing arm (53 percent vs. 45 percent, p = 0.06).
Donor T-cell depletion has been explored as a means of GVHD prevention, using either mechanical ex vivo T-cell depletion or in vivo T-cell depletion in the form of ATG or alemtuzumab. T-cell-depletion strategies have generally been successful in reducing GVHD, but in many instances the reduction in donor T cells contributes to an increased incidence of graft rejection, infection, and relapse which may negate the advantage of GVHD prevention. A recent randomized clinical trial of ATG versus placebo added to standard CSP/MTX GVHD prophylaxis reported lower rates of acute and chronic GVHD in the ATG arm, although TRM and overall survival were not improved.373 Longer followup from this study confirmed a significantly lower rate of chronic GVHD in the ATG arm (45 percent vs. 12 percent, p <0.0001).374 However, ATG was associated with an increased risk of PTLD, a complication that is virtually nonexistent after T-cell-replete allogeneic HCT. In fact, there were 4 deaths from PTLD in the ATG arm (versus none in the placebo arm). Perhaps as a result, the study did not show improvements in TRM or overall survival with ATG. A subsequent randomized clinical trial aimed at replicating and extending these results with ATG has been completed in the United States.
In the setting of reduced-intensity allotransplantation, a number of immunosuppressive regimens have been used, the most common being CSP plus MMF.177,185 Posttransplant CY has demonstrated impressive efficacy in the setting of HLA-haploidentical HCT, and has been studied in the setting of HLA-matched allotransplantation as well.375,376 The combination of TLI and ATG is associated with very low rates of acute and chronic GVHD even with standard CSP/MMF postgrafting immunosuppression,184,185 suggesting that protective conditioning can play a significant role in GVHD prevention.
Several laboratories have reported that naïve (CD62L+) T cells induce experimental acute GVHD, whereas effector memory (CD62L–) T cells do not.377,378 Based on this insight, depletion of naïve donor T cells has been investigated as a means of preventing acute GVHD in humans.379 Murine models of marrow transplantation show that simultaneous infusions of Treg limited the proliferation and clonal expansion of activated donor T cells and protected against acute GVHD development in murine models.144 Pilot studies of Treg infusions in humans have demonstrated safety and some efficacy in preventing GVHD,145,146,380 although larger trials are required to confirm these preliminary findings. Importantly, relapse rates did not appear to be increased by the addition of Treg, consistent with murine models.144,146
Another investigational avenue in GVHD prevention involves inhibition of lymphocyte trafficking through CCR5 blockade. A recent trial combining the CCR5 antagonist maraviroc with standard GVHD prophylaxis demonstrated low rates of acute GVHD, particularly GI GVHD.381 The BMT-CTN is currently conducting a three-arm randomized clinical trial comparing novel approaches to GVHD prophylaxis: posttransplant CY; maraviroc; and bortezomib-based immunosuppression.
The standard first-line therapy for acute GVHD requiring systemic treatment is methylprednisolone or prednisone, at a dose of 1 to 2 mg/kg/day with subsequent tapering once disease activity resolves. Higher doses of methylprednisolone (10 mg/kg per day) do not prevent evolution to grades III to IV acute GVHD or improve survival.382 Patients with acute GVHD grade II or less can be safely treated with a starting dose of 1 mg/kg/day of methylprednisolone, an approach that reduces overall glucocorticoid exposure and toxicity.383 Complete resolution of acute GVHD is reported in less than 50 percent of patients after first-line treatment with glucocorticoids, and the likelihood for long-term survival is low among individuals who develop glucocorticoid-refractory acute GVHD.384 Various approaches, including third-party mesenchymal stem cells, MMF, and TNF blockade, have been combined with glucocorticoids in upfront treatment of acute GVHD, but none has proven superior to glucocorticoids alone.385,386
There is no standard second-line therapy for patients with glucocorticoid-refractory acute GVHD. Practices vary widely, although groups such as the ASBMT have published guidelines in an effort to codify and standardize treatment.387 Even though many agents have been used in this setting, none has proven superior or even reliably effective. Options include enrollment on a clinical trial, treatment with a second-line agent of choice, and palliative care. Agents that have been studied include daclizumab, SRL, MMF, ABX-CBL (a CD147-specific monoclonal antibody), anti-TNF agents, visilizumab, ruxolitinib,388,389 and ATG, among others. In the absence of comparative clinical trial data, the choice of second-line agent is often guided by institutional experience, physician preference, and side-effect profiles. Outcomes with second-line therapy remain poor, and novel treatments for glucocorticoid-refractory acute GVHD are needed.
CHRONIC GRAFT-VERSUS-HOST DISEASE
Chronic GVHD is the major determinant of quality of life in long-term survivors of allogeneic HCT.390,391 Despite its impact, however, it remains poorly understood and treatment options remain limited and largely empiric. Historically, any form of GVHD occurring beyond day +100 after allogeneic HCT was defined as chronic GVHD. However, with an increasing appreciation of the biologic differences between acute and chronic GVHD and the recognition that late acute GVHD occurs beyond day +100 with RIC, chronic GVHD was redefined on the basis of pathognomonic clinical and histologic criteria by a National Institutes of Health (NIH) consensus conference in 2005.360 The NIH consensus criteria include global and organ-specific scoring to evaluate the severity of chronic GVHD, and these staging tools have been validated to correlate with clinical severity and outcomes.392,393 The Center for International Blood and Marrow Transplant Research (CIBMTR) has also developed a chronic GVHD risk-stratification algorithm that identifies age, donor–recipient gender mismatch, serum bilirubin, platelet count, donor type, and performance status, among other factors, as predictors of outcome in patients with chronic GVHD.394 The presence of chronic GVHD is consistently associated with more potent GVT effects and a lower risk of posttransplantation relapse,177,395 although the negative impact of chronic GVHD on TRM may outweigh the benefit against relapse.177
In contrast to acute GVHD, which is limited to the skin, gut, and liver, chronic GVHD has diverse manifestations which can affect nearly any organ system and which overlap considerably with those of autoimmune disorders such as scleroderma, lichen planus, Sjögren syndrome, and dermatomyositis. The most common clinical features of chronic GVHD include lichenoid skin lesions that may progress to generalized scleroderma, keratoconjunctivitis sicca, lichenoid oral lesions, esophageal and vaginal strictures, intestinal abnormalities, chronic liver disease, and bronchiolitis obliterans. Comprehensive assessment of chronic GVHD requires a detailed history and physical examination, but can be performed in the clinic in less than 20 minutes.396 Instructional videos and training tools demonstrating clinical assessment of chronic GVHD are available.397
The pathophysiology of chronic GVHD remains poorly understood. In contrast to acute GVHD, where there is a track record of translation from relevant animal models to humans, existing murine models of chronic GVHD suffer from serious shortcomings,398 limiting the understanding of its pathobiology and restricting the study of novel therapies. Efforts continue to develop more relevant murine models,399 although translational success remains elusive.
Although chronic GVHD is frequently preceded by acute GVHD, progress in reducing the incidence of acute GVHD has generally not translated into a reduction in the incidence of chronic GVHD. If anything, the incidence of chronic GVHD is likely increasing, as a result of the increasing use of PBPC as a graft source and the increasing at-risk pool of long-term survivors of allogeneic HCT. The only approaches proven to prevent chronic GVHD are the use of marrow as a graft source rather than PBPC,72 and the use of ex vivo or in vivo T-cell depletion (which carries increased risks of infection, PTLD, and relapse).373,400 It has been suggested that posttransplant CY may prevent chronic GVHD, as low rates have been reported in single-arm studies,375,376 but this comparison is confounded by graft source (predominantly marrow in trials of posttransplant CY) and requires confirmation in randomized clinical trials. Recipient statin use has been associated with a significantly reduced risk of chronic GVHD, but a higher risk of relapse, in patients receiving CSP-based GVHD prophylaxis regimens.401 Rituximab has been studied as a prophylactic agent because of the demonstrated role of B cells in the genesis of chronic GVHD. Results have been mixed; a clinical trial performed at Stanford University demonstrated that rituximab potently abrogated B-cell alloimmunity, but did not lead to a statistically significant reduction in chronic GVHD incidence.402 A nonrandomized study from the Dana-Farber Cancer Institute reported that rituximab decreased glucocorticoid-requiring chronic GVHD (but not overall chronic GVHD incidence) in comparison with a concurrent control cohort,403 a finding which requires confirmation in randomized clinical trials.
Despite decades of investigation of novel therapies, the standard of care for initial systemic treatment of chronic GVHD remains prednisone 1 mg/kg/day, with or without a calcineurin inhibitor.404 Numerous investigational agents have demonstrated promise in uncontrolled phase II clinical trials. However, these agents have uniformly proven disappointing when subjected to randomized phase III studies. At least six large randomized trials conducted over the past 20 years testing various alternate regimens, including azathioprine, thalidomide, MMF, and hydroxychloroquine, have failed to demonstrate the efficacy of any novel regimen for treatment of established chronic GVHD.405,406,407,408,409,410
Patients with chronic GVHD typically require prolonged courses of immunosuppressive therapy. The median time to discontinuation of all systemic immunosuppression in patients with chronic GVHD resolution is approximately 2 years.411 Approximately half of patients with chronic GVHD will fail to respond to glucocorticoids and require second-line therapy.412 As with acute GVHD, there is no single standard of care for glucocorticoid-refractory chronic GVHD, and enrollment on a clinical trial should be strongly considered. Treatment choice depends on patient and physician preference, side-effect profile, and institutional priorities, as there are no data to guide a more systematic approach. Typical second-line agents include extracorporeal photopheresis (ECP), SRL, thalidomide, pentostatin, rituximab, and imatinib, among others.412 ECP is logistically cumbersome but can be effective and causes relatively few adverse effects413; this approach is currently being studied in a randomized clinical trial conducted by the BMT-CTN. Low-dose IL-2 has been reported to facilitate Treg expansion and homeostasis in a small single-center study of patients with chronic GVHD,414,415 although the degree of Treg expansion was not significantly associated with clinical response.414 Nonetheless, therapies targeting Tregs are under active investigation in the treatment of chronic GVHD, as is the Bruton tyrosine kinase inhibitor ibrutinib.416 More effective prevention and treatment of chronic GVHD remains a crucial research need in allogeneic HCT.
RELAPSED MALIGNANCY AFTER HCT
Relapse following autologous or allogeneic HCT is an ominous clinical event. Every effort should be made to verify relapse pathologically, as it is common for patients to have residual radiographic abnormalities following transplantation, especially in patients with lymphoma. Patients with myeloma have gradual reductions in biochemical markers of disease which may take several months after autologous HCT to reach maximal response. Following RIC, the allogeneic GVT effect may take weeks to months to result in tumor eradication, and it may be difficult to distinguish persistent yet slowly regressing disease from slowly progressive disease, particularly with indolent NHL or CLL.
Relapse after Autologous Hematopoietic Cell Transplantation
Disease relapse remains the most common cause of treatment failure after autologous HCT. Relapse often occurs at sites of previous disease, suggesting that residual disease within the patient rather than autograft contamination is responsible.417 Additional cytotoxic chemotherapy alone is highly unlikely to be curative in patients relapsing after autologous HCT, as the disease has already survived supralethal doses of chemotherapy. Treatment options for patients with relapse after autologous HCT include irradiation, immunomodulators, and/or targeted therapies. For selected patients, salvage allogeneic HCT may be feasible using RIC. Strategies to reduce the risk of relapse in high-risk patients undergoing autologous HCT include consolidative involved-field radiotherapy, antitumor vaccination,418 maintenance therapy with targeted agents,269,419,420 and planned tandem allogeneic HCT.421
Relapse after Allogeneic Hematopoietic Cell Transplantation
Treatment of disease relapse following allogeneic HCT is generally unsuccessful. In particular, patients with high-risk malignancies and early relapse (<100 days after allogeneic HCT) have a dismal prognosis, with 2-year overall survival of less than 5 percent.422 Salvage chemotherapy can result in disease responses, but they are unlikely to be durable. Performing a second myeloablative transplantation procedure has largely been unsuccessful because of excessive toxicity and TRM of greater than 50 percent. More recently, selected patients have been treated with a second allogeneic HCT using RIC. Treatment-related toxicity with this approach is not prohibitive and successful disease eradication has been reported, although relapse remains the major cause of death.423 There is no consensus on whether to use the same donor or a different donor for second-salvage allogeneic HCT in the setting of relapse. More importantly, the majority of patients with relapse after allogeneic HCT are ineligible for second allotransplant because their diseases cannot be adequately controlled or cytoreduced. Experimental therapies with chimeric antigen receptor-bearing autologous T cells or other investigational approaches warrant consideration in these cases. In our view, palliative care is a reasonable option, particularly in the setting of early or chemorefractory relapse after allogeneic HCT, and should be presented to patients.
In the setting of retained donor T-cell chimerism, posttransplantation relapse has sometimes been treated by rapidly tapering immunosuppressive medications to stimulate a GVT effect. Although this approach is occasionally successful in patients with indolent malignancies such as low-grade NHL or CLL, it is rarely effective against more aggressive diseases such as acute leukemias, and carries a high risk of precipitating severe GVHD.
In patients who are off immunosuppression without evidence of GVHD at the time of relapse, DLI has been used to augment GVT. The mechanism by which DLI works is unclear; it may normalize the T-cell repertoire or reverse so-called T-cell “exhaustion.”424,425 Historically, the best outcomes for DLI have been reported for CML, although TKIs have supplanted DLI for the most part in this setting.426 DLI alone is typically insufficient to control aggressive hematologic malignancies,427 and thus patients are often treated with reinduction chemotherapy or other cytoreduction before receiving DLI as consolidation.
The major potential adverse effects of DLI are GVHD and marrow aplasia. The risk of GVHD after DLI is at least 20 percent and likely as high as 50 to 70 percent.428,429 Marrow aplasia typically occurs in the setting of residual host hematopoiesis; when host HSC are eradicated by DLI, there may be too few donor HSC to support hematopoietic recovery and prolonged aplasia (>6 weeks) can ensue.430 Thus, chimerism should be evaluated before DLI, and DLI should be used with caution in patients with significant residual host hematopoiesis. There are limited data on the optimal cell dose of DLI. In a retrospective analysis, doses greater than 1 × 108 CD3+ cells/kg were associated with a high risk of GVHD (55 percent) without a corresponding benefit in disease control, while doses of 1 × 107 CD3+ cells/kg or less were associated with the lowest rates of GVHD (21 percent).428 Modifications of DLI, including selection of CD8+ effector lymphocytes or production of cytokine-induced killer cells,141 are under investigation to improve the safety and efficacy of this approach.