Managing the Toxicity of Hematopoietic Stem Cell Transplant
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R E V I E W
An Organ-Specific Review
Managing the Toxicity of
Hematopoietic Stem Cell Transplant
Arnel M. Pallera, MD, and Lee S. Schwartzberg, MD, FACP
T
he availability of hematopoietic stem cells
to rescue otherwise lethally myelotoxic Abstract Hematopoietic stem cell transplant is an established treatment
chemotherapy is the fundamental mecha- modality for a variety of neoplastic, hematologic, and immunologic disor-
nism behind stem cell transplantation. ders. Fueled in part by remarkable technologic advances, the number of
Indeed, the specific nonhematologic toxicities de- both autologous and allogeneic transplants has increased dramatically
scribed in this review ultimately limit escalation of over the past decade. Peripheral blood stem cells have largely replaced
various chemotherapeutic agents due to extramed- bone marrow as the source of hematopoietic progenitors in autologous
ullary maximally tolerated dosages. Abrogation of transplants, and their use in the allogeneic setting has increased sub-
myelotoxicity allows a severalfold increase in the stantially. Less toxic transplants, in the form of non-myeloablative con-
standard doses of various drugs, particularly alkyl- ditioning regimens, are being actively investigated, with the promise of
ating agents, heightening the therapeutic effect of expanding indications and age limits for allogeneic transplant. A suc-
the regimen. In allogeneic transplant, the condi- cessful global infrastructure allowing sharing of HLA-typing information
tioning regimen concurrently causes host immu- has led to increased availability of non-sibling, HLA-matched, unrelated
nosuppression, permitting the donor progenitor donor transplants for many patients who lack a suitable sibling donor.
cells to successfully engraft in the bone marrow Finally, umbilical cord blood transplants are being investigated in both
and reconstitute the recipient’s hematoimmuno- children and adult patients. The ability to transplant more individuals
poietic system. with broader indications owes much to a concurrent improvement in
supportive care agents and techniques. Although regimen-related mor-
Infectious Complications tality and morbidity have decreased, stem cell transplants continue to
After stem cell transplant, there is an obligate pose multiple potential complications. A careful proactive assessment
period of pancytopenia, when the risk for infec- to identify, treat, and, hopefully, prevent adverse events is essential to a
tion is high. Early on, in the first 4 weeks after successful transplant. This review is intended to summarize some of the
hematopoietic stem cell transplant, bacterial in- toxicities of hematopoietic stem cell transplant in a systematic, organ-
fections and invasive fungal infections predomi- based fashion and to review the treatment options available for each of
nate. Between 30 and 100 days after transplant, these side effects.
impaired cellular immunity leads to an increased
incidence of viral infections. After 100 days, par-
ticularly in allogeneic transplant patients, who cell transplant recipients summarized in Table 1 Dr. Pallera is a partner
have ongoing impaired cellular and humoral im- [1]. The treatment of infections in stem cell recip- at The West Clinic,
Memphis, Tennessee,
munity, there is risk for opportunistic infections ients involves an understanding of clinical infec- and Director of
from less pathogenic bacteria and fungi and from tion syndromes, the natural history of individual Allogeneic Transplant
viral reactivation. infections in the context of immune suppression Services of the Stem Cell
Each phase of the post-transplant period should after transplant, and the mechanisms of immune Transplant Program at
Baptist Cancer Institute,
have associated preventive strategies and a high system reconstitution over time (Table 2). Memphis.
index of suspicion for infectious etiologies. The
Centers for Disease Control and Prevention has Pre-Engraftment Risk Period Dr. Schwartzberg is
recently published comprehensive guidelines for The pre-engraftment risk period begins with Medical Director of The
West Clinic and Director
preventing infections among hematopoietic stem the onset of conditioning therapy and continues of the Stem Cell
until approximately 30 days after transplanta- Transplant Program at
Correspondence to: Lee S. Schwartzberg, MD, The West tion. The conditioning regimen can cause severe Baptist Cancer Institute.
Clinic, 100 N. Humphreys Boulevard, Memphis, TN 38120; neutropenia, as well as defects in mucosal and
telephone: (901) 683-0055; fax: (901) 685-9718; e-mail: cutaneous barriers from mucositis or the place-
lschwartzberg@westclinic.com
ment of central venous catheters. These abnor-
J Support Oncol 2004;2:223–247 © 2004 BioLink Communications, Inc. malities commonly lead to bacterial and fungal
VOLUME 2, NUMBER 3 ■ MAY/JUNE 2004 www.SupportiveOncology.net 223bloodstream infections. Gram-positive organisms
Table 1 cause one half of the bacteremias occurring after
Updated Recommendations for the Prevention of Opportunistic a bone marrow transplant [2]. Staphylococcus epi-
Infections After Hematopoietic Stem Cell Transplant (HSCT)a dermidis is the species most commonly recovered
in culture, followed by Streptococcus pyogenes, S
Prevention of cytomegalovirus (CMV) infection pneumoniae, and Enterococcus spp. Gram-negative
Prevention of exposure: organisms are also common causes of bloodstream
• Test recipient and donor immunoglobulin (IgG) serostatus infection. Candida infections can occur during
• Seronegative or leukocyte-depleted blood to seronegative allograft recipients
• Counseling seronegative recipient on mode of CMV transmission and risk-lessening this risk period and arise from endogenous organ-
behavior isms colonizing the patient’s gastrointestinal (GI)
Prevention of disease or recurrence: tract.
• Ganciclovir prophylaxis or preemptive therapy based on antigenemia or DNA Two large randomized, placebo-controlled tri-
detection between engraftment and day 100 for high-risk patients
• Preemptive therapy based on antigenemia or DNA detection between engraftment als have shown that the prophylactic use of fluco-
and day 100 in seronegative recipients with seropositive donors nazole (Diflucan) in stem cell recipients confers a
Prevention of herpes simplex virus (HSV) infection decreased risk for superficial and invasive fungal
Prevention of exposure: infections [3, 4]. Hence, it is now routine in many
• Test recipient IgG serostatus transplant centers to give antifungal prophylaxis
• Counseling of seronegative recipient on transmission and risk-lessening behavior
• Contact isolation for persons with disseminated severe or severe mucocutaneous
after hematopoietic stem cell transplant. Herpes
HSV disease simplex virus infection is also common and can
Prevention of disease or recurrence: develop via reactivation in seropositive patients.
• Acyclovir prophylaxis in seropositive allograft recipients By initiating acyclovir prophylaxis, this reactiva-
Prevention of varicella-zoster virus (VZV) infection tion rate can be reduced substantially [5, 6].
Prevention of exposure:
• Test recipient IgG serostatus Post-Engraftment Risk Period
• Counseling of strategies to prevent exposure
• Vaccination of family members and close household contacts who are seronegative The post-engraftment risk period begins with
or have no history of VZV exposure neutrophil recovery and continues until B- and T-
• Respiratory and contact isolation of HSCT recipients with VZV
Prevention of disease or recurrence:
lymphocyte recovery is apparent (usually around
• Varicella-zoster immunoglobulin within 96 hours for VZV-seronegative recipients day 100). It is during this period that cytomegalo-
following VZV exposure virus (CMV) infection has its highest incidence.
Prevention of community respiratory virus infection This infection can occur either as a primary infec-
Prevention of exposure: tion in seronegative patients or by reactivation in
• Targeted surveillance system for respiratory viruses seropositive patients. The use of seronegative or
• Contact isolation of HSCT recipients with respiratory symptoms
Prevention of disease or recurrence: leukocyte-filtered blood products for transfusions
• Influenza vaccination of HSCT recipients is not recommended < 6 months after has reduced the incidence rate of primary CMV
transplant infection from 40% to 3% in seronegative recipi-
Prevention of invasive fungal infections ents [7]. Further, prevention strategies based on
• Hand washing to prevent spread of exogenous Candida species either antigenemia or the polymerase chain reac-
• Fluconazole (400 mg/d) recommended to prevent invasive yeast infection
• Patients are to avoid hospital construction or renovation areas
tion (PCR) and the subsequent use of antiviral
Prevention of bacterial infections agents such as ganciclovir or foscarnet (Foscavir)
All bacteria: decreases morbidity and mortality from CMV
• Hand washing is the single, most important intervention infection [8].
Haemophilus influenzae: Aspergillus infections also can occur during
• Vaccinate contact
this time in patients who are receiving high-dose
• Vaccinate HSCT recipient at 12, 14, and 24 months
Streptococcus viridans: corticosteroids and in those with ongoing graft-
• Resolve dental problems before HSCT versus-host disease. With the use of fluconazole
Prevention of protozoal infections prophylaxis, invasive aspergillosis has emerged as
Pneumocystis carinii: the fungal infection most often found at autopsy
• Prophylaxis from engraftment to 6 months (trimethoprim/sulfa drug of choice) in bone marrow transplant recipients. This infec-
• Longer course if graft-versus-host disease is present or immunosuppressive therapy
is continued tion is usually treated with aggressive agents such
as amphotericin B alone or in combination with
a
Joint recommendations of the Centers for Disease Control and Prevention, the Infectious Diseases Society of
America, and the American Society of Blood and Marrow Transplantation. one of the newer antifungal agents, such as vori-
Adapted from Sullivan et al [1] conazole (Vfend). However, the mortality rate for
224 www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGYTable 2 Pallera
Phases of Infection Among Hematopoietic Stem Cell Transplant Recipients Schwartzberg
PHASE I PHASE II PHASE III
Onset Pre-engraftment, < 30 days Post-engraftment, 30–100 days Late phase, > 100 days
Immune Neutropenia, skin/mucosa Mucositis, acute GVHD, Impaired cellular and humoral
defects barrier, acute GVHD impaired cellular immunity immunity, chronic GVHD
Infectious Bacteria Bacteria Bacteria
agents Streptococcus spp Staphylococcus epidermidis Encapsulated bacteria
Staphylococcus aureus Fungi Fungi
Staphylococcus epidermidis Aspergillus sp Aspergillus sp
Facultative gram-negative Candida sp Protozoa
bacteria Viruses Pneumocystis carinii
Clostridium difficile Cytomegalovirus Viruses
Enterococcus spp Cytomegalovirus
Fungi Varicella-zoster virus
Aspergillus sp
Candida sp
Viruses
Herpes simplex virus
Respiratory syncytial virus
Influenza virus
GVHD = graft-versus-host disease
patients with this disease is still very high, with es- ribavirin (Virazole) or intravenous immune globu-
timated 1-year survival rates of less than 10% [9]. lin [11]. Due to the present practice of adminis-
tering extended ganciclovir prophylaxis, CMV
Late Post-Transplantation Risk Period disease may also develop in this late period.
The late post-transplantation risk period be- An uncommon complication of hematopoietic
gins at approximately day 100 and ends when the stem cell transplant seen predominantly in allo-
patient discontinues immunosuppressive therapy. geneic transplants is Epstein-Barr virus (EBV)-
Encapsulated bacteria, including S pneumoniae, associated post-transplantation lymphoprolifera-
are common agents of infection in this period due tive disorder (PTLD). The etiology of PTLD stems
to functional hyposplenism. Further, Aspergillus from latent proliferation of B cells infected with
is also common due to prolonged immunosup- EBV in the context of functionally inefficient or
pression from graft-versus-host disease. Another reduced numbers of modifying T cells. Risk factors
common infection during this period and the post- include HLA-matched, unrelated donor or mis-
engraftment period is Pneumocystis carinii pneumo- matched sibling transplants, total body irradiation
nia. However, prophylaxis with trimethoprim and in the conditioning regimen, and T-cell–depleted
sulfamethoxazole at the time of engraftment has grafts [12]. Clinical presentation includes multi-
substantially decreased the incidence of this dis- focal lymphomatous masses in extranodal sites,
ease, and current cases are attributed to problems often with constitutional symptoms. The course
with compliance to the prophylactic schedule. is often rapidly progressive, with a peak onset of
There are also several viruses, such as varicella- symptoms approximately 3 months after allogeneic
zoster virus (VZV), that can lead to severe infec- transplant. The syndrome may be occult and may
tions during the late post-transplant period. Infec- be undiagnosed prior to death. Histologically, the
tion with VZV occurs with a median time of onset lymphomatous masses may be polyclonal, mono-
of 5 months after transplantation and, when dis- clonal, polymorphic, or monomorphic.
seminated, is associated with a substantial mortal- Treatment of PTLD has been somewhat disap-
ity rate [10]. High-dose acyclovir is the treatment pointing. Reducing immunosuppressive therapy
of choice for this infection. Respiratory viruses, is the first step, but it is rarely effective by itself. Peer viewpoints on this
such as respiratory syncytial virus or parainfluenza Rituximab (Rituxan), an anti-CD20 monoclonal article by Drs. Thomas
virus, are common causes of respiratory tract infec- antibody, has been associated with complete re- C. Shea and Stephen
tions. When the lower respiratory tree is involved, sponses in the neighborhood of 50%. Adoptive J. Forman appear on
high mortality rates occur despite therapy with cellular therapy employing donor lymphocyte pages 237 and 241.
VOLUME 2, NUMBER 3 ■ MAY/JUNE 2004 www.SupportiveOncology.net 225infusions may control PTLD, but at the expense and vomiting [14]. In a recent prospective study,
Hematopoietic of increasing the risk of graft-versus-host disease. virtually all patients receiving myeloablative-
Stem Cell Ex vivo, EBV-specific, cytotoxic T lymphocytes conditioning regimens experienced oral mucositis,
may be effective, but these cells are technically with half the patients needing parenteral opioid
Transplant
difficult to produce. Cytotoxic chemotherapy is analgesia for a median of 6 days [15].
compromised by hematologic toxicity in the post- It is vital to provide adequate pain relief for mu-
transplant period. cositis during the immediate post-transplant peri-
Thrombotic microangiopathic anemia, char- od. Patient-controlled analgesia with intravenous
acterized by unexplained thrombocytopenia, morphine or hydromorphone in conjunction with
elevated lactate dehydrogenase levels, and topical anesthetics is most useful. Specific mea-
schistocytosis on peripheral blood smears in the sures to prevent or ameliorate mucositis resulting
setting of normal coagulation studies, is common- from high-dose chemotherapy have not been es-
ly detected in allogeneic hematopoietic stem cell tablished, but promising trials with recombinant
transplant patients receiving either tacrolimus human keratinocytic growth factor-1 (palifermin)
(FK506, Prograf) or cyclosporin A immunosup- [16], other systemic cytokines, and oral agents,
pressive therapy. The syndrome has considerable such as pilocarpine (Salagen) and glutamine, are
overlap with acute graft-versus-host disease and being actively explored [17].
may also be caused by certain chemotherapeutic A pretreatment dental evaluation, targeting
agents, irradiation, and infections [13]. Renal oral hygiene, is critical for patients contemplating
insufficiency is found almost universally, so the hematopoietic stem cell transplant. Prophylaxis
disease falls into the category of hemolytic uremic with a chlorhexidine rinse is helpful [18]. The
syndrome and/or thrombotic thrombocytopenic high-dose chemotherapy regimen itself is an im-
purpura (TTP). Treatment with plasmapheresis portant determinant of the degree and time to on-
and plasma exchange, although frequently used, set of mucositis. Non-myeloablative regimens have
is rarely successful, perhaps reflecting a different the potential to substantially reduce this toxicity,
underlying etiology from the decreased levels of because they generally consist of lower, less toxic
von Willebrand factor cleaving protease seen in doses of drugs. Oral mucositis from hematopoietic
sporadic TTP. Removal of immunosuppressive stem cell transplant is associated with significantly
therapy and supportive measures should be in- worse clinical and economic outcomes, including
stituted after the diagnosis of thrombotic micro- longer hospitalization, a higher likelihood of mor-
angiopathic anemia. tality, and increased cost of transplant [19].
Gastrointestinal Toxicity NUTRITIONAL DEFICIENCIES
Gastrointestinal toxicity is the most common Most patients undergoing hematopoietic stem
regimen-related side effect of high-dose chemo- cell transplant develop anorexia, reduced calorie
therapy in hematopoietic stem cell transplant intake, and weight loss. Consequently, supple-
patients. Alkylating agents often affect the basal mental delivery of nutrition becomes essential in
layer of the mucosal lining, leading to mucositis, the course of treatment. Negative nitrogen bal-
diarrhea, nausea, and vomiting. As this toxicity ance, a catabolic state, expansion in extracellular
progresses, it may lead to colitis, typhlitis (inflam- fluid, vitamin deficiency, and trace-element defi-
mation of the terminal ileum), and esophagitis. ciency are all common after hematopoietic stem
Loss of mucosal integrity is synergistic with neu- cell transplant [20]. Supplemental nutrition after
tropenia in reducing the first line of defense of the transplant, utilizing either enteral nutrition or to-
immune system, leading to a risk of bacterial and tal parenteral nutrition (TPN), has been widely
fungal infections that are initially localized but adopted, especially in the allogeneic bone marrow
then often invade the bloodstream by breaching transplant setting, where graft-versus-host disease
the mucosa. also contributes to a higher likelihood of mucositis
and GI complications. In general, TPN appears to
MUCOSITIS maintain body weight better, but it has no impact
From the patient’s perspective, mouth sores rank on overall survival. On the negative side, TPN in-
as the single most debilitating side effect of hema- creases the risk for central venous catheter infec-
topoietic stem cell transplant, followed by nausea tions. In addition, the overall benefits of enteral
226 www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGYnutrition compared with parenteral nutrition are death before 100 days of ongoing veno-occlusive
still not well established, reflecting a need for fur- disease [23], occurs in 4%–19% of patients who Pallera
ther study. have received a stem cell transplant. The clinical Schwartzberg
onset usually occurs within 21 days after trans-
THE QUESTION OF GLUTAMINE plant, although some regimens are associated with
There has been substantial interest in study- a delayed onset of veno-occlusive disease or even
ing the addition of glutamine in hematopoietic a bimodal presentation [24].
stem cell transplant patients. Glutamine is a criti- A model to predict the severity of veno-
cally essential amino acid that regulates protein occlusive disease based on percentage of weight
degradation, prevents gut atrophy, and enhances gain and bilirubin level has been developed and
immune function [21]. A recent Cochrane re- validated [25]. However, to date no diagnostic
view [22] concluded that hematopoietic stem cell tests predict the onset of veno-occlusive dis-
transplant patients who are unable to tolerate oral ease, and heparin prophylaxis has generally been
or tube feeding are more likely to achieve earlier found to be ineffective in lowering its incidence
hospital discharge and have fewer positive blood or mortality. Ursodiol (ursodeoxycholic acid)
cultures if they receive parenteral nutrition plus has lowered the incidence of moderate or severe
glutamine compared with standard TPN. To date, veno-occlusive disease in some randomized trials
a standard dose of glutamine has not yet been [26]. A variety of other treatments have been at-
determined, and glutamine supplementation re- tempted for established veno-occlusive disease,
mains an area of active investigation. with generally disappointing results. The thrust
has been to lessen endothelial damage without
LIVER TOXICITY inducing systemic bleeding. Antithrombin III,
The liver is a frequent target of toxicity from tissue-type plasminogen activator (tPA), and
high-dose chemotherapy in hematopoietic stem heparin have all been used, with intermittent suc-
cell transplant. Multiple etiologies of liver dysfunc- cess but a high risk of hemorrhagic complications.
tion include bacterial sepsis, TPN, viral infection, Transhepatic shunts and liver transplants are inef-
congestive heart failure, and acute graft-versus- fective for established veno-occlusive disease, but
host disease. A common, potentially serious com- recently a multicenter clinical trial [27] of defi-
plication of stem cell transplant is veno-occlusive brotide, a single stranded deoxyribonucleotide,
disease of the liver. The features of this clinical showed promise.
syndrome include:
• hyperbilirubinemia > 2 mg/dL with jaundice; Graft-Versus-Host Disease
• hepatomegaly and right upper quadrant Graft-versus-host disease is the major compli-
pain; and cation of allogeneic bone marrow transplantation.
• ascites and sudden weight gain > 5% above It is a consequence of donor T cells recognizing
baseline. host-recipient antigens as foreign. The factors
The pathophysiology of veno-occlusive disease necessary for graft-versus-host disease to develop
includes endothelial damage, sinusoidal fibrosis in include immunocompetent donor T cells, histo-
zone 3 of the liver acinus, microthrombosis, fibrin incompatibility between the donor and the host,
deposition, and, ultimately, hepatocyte necrosis. and immunoincompetence of the recipient. This
Predisposing factors to veno-occlusive disease of disease is initiated during the conditioning of the
the liver include preexisting liver dysfunction, an patient, when host tissues are damaged and the
HLA mismatched or unrelated donor transplant, recipient is rendered immunodeficient. The affer-
advanced disease status at the time of transplant, ent phase of this disease occurs when alloreactive
and the type of chemotherapy used in the con- donor T lymphocytes recognize the major and mi-
ditioning regimen. Veno-occlusive disease occurs nor histocompatibility antigens of the host tissues
in 0% to 70% of patients receiving hematopoietic as foreign, resulting in T-cell activation and pro-
stem cell transplant, depending upon the meth- liferation. This process leads to an efferent phase
odology used to define the syndrome as well as of graft-versus-host disease, characterized by cyto-
heterogeneity in transplant regimens and patients. kine secretion and an inflammatory cascade that
Severe veno-occlusive disease, defined as liver induces pathology in multiple organ systems.
dysfunction that fails to resolve despite therapy or There are several pretransplant risk factors
VOLUME 2, NUMBER 3 ■ MAY/JUNE 2004 www.SupportiveOncology.net 227Table 3
Grading of Acute Graft-Versus-Host Disease (GVHD)
SEVERITY OF INDIVIDUAL ORGAN INVOLVEMENT
Skin +1 A maculopapular eruption involving less than 25% of the body surface
+2 A maculopapular eruption involving 25%–50% of the body surface
+3 Generalized erythroderma
+4 Generalized erythroderma with bullous formation, often with
desquamation
Severity of Acute GVHD
Liver +1 Moderate increase of SGOT (150–750 IU) and/or bilirubin (2.0–3.0 mg/dL)
+2 Bilirubin increase (3.1–5.9 mg/dL) OVERALL ORGAN GRADE (SEE TABLE AT LEFT)
+3 Bilirubin increase (6.0–14.9 mg/dL) GRADE SKIN LIVER GI TRACT
+4 Bilirubin increase > 15 mg/dL 0 0 0 0
GI tract +1 Stool > 500 mL/d 1 1 or 2 0 0
+2 Stool > 1,000 mL/d 2 1, 2, or 3 1 1
+3 Stool > 1,500 mL/d 3 2 or 3 2 or 3 2 or 3
+4 Stool > 2,000 mL/d or severe abdominal pain, with or without ileus 4 2, 3, or 4 2, 3, or 4 2, 3, or 4
SGOT = serum glutamic-oxaloacetic transaminase
for graft-versus-host disease. The most powerful of recipients of histocompatible sibling-matched
Hematopoietic factor is HLA disparity between the donor and allografts, and mortality due directly or indirect-
Stem Cell transplant recipient. However, significant graft- ly to graft-versus-host disease may be as high as
versus-host disease also occurs in 25%–60% of 50% [30].
Transplant
HLA-matched related recipients and 45%–70% Skin. In general, the first and most common
of HLA-matched unrelated transplant recipients clinical manifestation of acute graft-versus-host
[28]. Age is another major risk factor for graft- disease is a maculopapular rash, with a median
versus-host disease. The incidence of significant onset 19 days after transplantation. Pruritus in-
acute graft-versus-host disease in myeloablative volving the palms of the hands and soles of the
transplants is approximately 20% in transplant re- feet often develops, and a sense of nasal stuffiness
cipients aged 20 years and younger, approximately may precede the rash. In its early stages, the rash
20%–30% in patients 21–50 years, and 79% in may involve the nape of the neck, ears, shoul-
those aged 51–62 years [29]. Factors that lower ders, palms, and soles. As the disease progresses,
the incidence of graft-versus-host disease include the rash becomes more confluent, and it can
a nulliparous donor, a T-cell–depleted graft, an spread to total body erythroderma. In severe cas-
umbilical cord blood transplant, and a gender- es, bullous formation and severe desquamation
matched transplant. may occur. Histologically, the epidermis and hair
Graft-versus-host disease is divided into acute follicles are damaged and sometimes destroyed
and chronic phases. Acute graft-versus-host dis- [31]. A sparse lymphocytic infiltrate, basilar vac-
ease is defined as signs and symptoms developing uolization, and, in severe cases, separation at the
less than 100 days after an allogeneic stem cell dermal-epidermal junction can be seen.
transplant, whereas chronic graft-versus-host dis- Liver. After the skin, the liver is the organ most
ease begins after 100 days. Obviously, some over- frequently involved in acute graft-versus-host dis-
lap between acute and chronic versions of this ease. The most common laboratory abnormality
disease exists. Patients may exhibit acute graft- is a rise in conjugated bilirubin and alkaline phos-
versus-host disease, chronic graft-versus-host dis- phatase levels. Histologically, varying degrees of
ease, or both. hepatocellular necrosis are seen. Involvement of
the portal tract is common, with degrees of dam-
ACUTE GRAFT-VERSUS-HOST DISEASE aged bile-duct epithelium ranging from single-cell
Acute graft-versus-host disease is a clinical- necrosis to complete obliteration of the bile epi-
pathological syndrome principally involving the thelium [32]. The differential diagnosis includes
skin, liver, GI tract, and immune system. Acute hepatic veno-occlusive disease, infection, and
graft-versus-host disease develops in 30%–60% drug toxicity.
228 www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGYGastrointestinal tract. Another target organ in
acute graft-versus-host disease is the GI tract. Table 4 Pallera
Clinically, GI involvement is characterized by Clinical-Pathological Classification of Schwartzberg
diarrhea and abdominal cramping. The diarrhea Chronic Graft-Versus-Host Disease (GVHD)
may be voluminous and bloody, causing life-
threatening fluid and electrolyte losses. A para- Limited chronic GVHD
lytic ileus may occur. Extensive damage to the Localized skin involvement
GI tract provides a portal of entry for infections. and/or
Histologically, destruction of intestinal crypts and Hepatic dysfunction due to chronic GVHD
subsequent mucosal ulcerations are seen. Graft- Extensive chronic GVHD
versus-host disease involving the GI tract should Generalized skin involvement
or
always be suspected when a transplant recipient
Localized skin involvement and/or hepatic dysfunction
presents with diarrhea in the context of white- due to chronic GVHD
blood-cell recovery. The differential diagnosis in- plus one or more of the following:
cludes chemotherapy-induced diarrhea, infection • Liver histology showing chronic aggressive hepatitis,
(eg, Clostridium difficile colitis or CMV infection), bridging necrosis, or cirrhosis, or
and other medications. A gentle sigmoidoscopy • Involvement of the eye (Schirmer’s test with less than
and biopsy can be helpful if the diagnosis is not 5 mm wetting), or
clear. When a diagnosis of graft-versus-host dis- • Involvement of minor salivary glands or oral mucosa
demonstrated on labial biopsy, or
ease is made, corticosteroids should be adminis-
• Involvement of any other target organ
tered promptly.
Immune system. Acute graft-versus-host disease
also results in lymph node and thymic involution, graft-versus-host disease ranged from 28% for no
inversion of the CD4/CD8 ratio, hypogamma- antecedent acute graft-versus-host disease to 85%
globulinemia, anergy, and an absence of an im- for patients with grade-4 acute graft-versus-host
mune response to vaccination. Thus, independent disease [32]. Other factors that increase a patient’s
of immunosuppressive therapy, acute graft-versus- risk for chronic graft-versus-host disease include
host disease results in profound immunosuppres- HLA disparity, age older than 20 years, the use
sion and susceptibility to infection. of a non–T-cell depleted bone marrow, and allo-
Acute graft-versus-host disease is graded ac- matched female donors for male recipients.
cording to the criteria listed in Table 3. Clini- Skin. A variety of organ systems are involved
cally significant acute graft-versus-host disease is in chronic graft-versus-host disease. Skin involve-
usually defined as an overall grade 2–4. Although ment occurs in about 75% of chronic graft-versus-
mild graft-versus-host disease (grade 1–2) is as- host disease cases and may be generalized or lo-
sociated with low morbidity and mortality, higher calized. Skin changes resemble lichen planus with
grades are associated with decreased survival. papulosquamous dermatitis, plaques, desquama-
With grade-4 graft-versus-host disease, the mor- tion, dyspigmentation, and vitiligo [31]. Destruc-
tality is in excess of 80%. tion to the dermal appendages leads to alopecia
and onychodysplasia. Severe chronic skin graft-
CHRONIC GRAFT-VERSUS-HOST DISEASE versus-host disease later resembles scleroderma,
Chronic graft-versus-host disease is a syndrome with indurations, joint contractures, and chronic
characterized by a primary or continued attack of skin ulcerations.
the graft on host tissues that can affect virtually Ocular and oral involvement in chronic graft-
any organ system. It usually presents more than 100 versus-host disease is also common. Lymphocytic
days after allogeneic bone marrow transplantation destruction of the exocrine glands results in a sicca
and occurs in as many as 50%–60% of patients. It is syndrome with atrophy and dryness of the mucosal
classified according to Table 4, with limited disease surfaces. Ocular symptoms include dry eyes, con-
associated with minimal morbidity and extensive junctivitis, photophobia, blurry vision, and corneal
disease associated with a decreased survival rate. erosions. Oral chronic graft-versus-host disease
The most important risk factor for chronic graft- results in xerostomia, poor dentition, and a loss of
versus-host disease is acute graft-versus-host dis- taste. The buccal mucosa may have a lacy white ap-
ease. In one study, the 3-year probability of chronic pearance as a sign of oral graft-versus-host disease.
VOLUME 2, NUMBER 3 ■ MAY/JUNE 2004 www.SupportiveOncology.net 229Gastrointestinal tract. The GI tract is frequently graft-versus-host disease is still a difficult problem
Hematopoietic affected by chronic graft-versus-host disease. to manage and is associated with substantial mor-
Stem Cell Hepatic function tests show a predominantly bidity and high mortality.
cholestatic picture. Small bowel and colonic in-
Transplant TREATMENT OF CHRONIC
volvement results in diarrhea and abdominal pain,
GRAFT-VERSUS-HOST DISEASE
whereas esophageal involvement can lead to the
formation of webs or narrowing, causing dysphagia Treatment of chronic graft-versus-host disease
or heartburn. also consists of immunosuppressive therapy. The
Other manifestations. Virtually every organ sys- most common modality again includes continued
tem can be affected by chronic graft-versus-host use of cyclosporine and/or tacrolimus and steroids.
disease. Other manifestations include the devel- Other agents, such as thalidomide (Thalomid),
opment of bronchiolitis obliterans, profound im- antithymocyte globulin, and azathioprine, have
munodeficiency, arthritis, arthralgias, and gyne- been used with varying success [35]. For steroid-
cologic symptoms, such as vaginal stenosis and refractory cases, other therapies such as rapamy-
dryness. Further, membranous nephropathy, thy- cin, PUVA therapy, hydroxychloroquine, extra-
roiditis, myasthenia gravis, and idiopathic throm- corporeal photophoresis, rituximab, daclizumab
bocytopenic purpura have been seen in associa- (Zenapax), pentostatin (Nipent), and infliximab
tion with chronic graft-versus-host disease. This (Remicade) have been attempted, with success
disease has been associated with autoantibody rates of 25%–50% [36].
formation, and, in fact, aspects of chronic graft-
versus-host disease may mimic systemic lupus Pulmonary Toxicity
erythematosus, scleroderma, rheumatoid arthritis, Pulmonary complications of hematopoietic
and other connective tissue diseases. stem cell transplant remain an important concern,
accounting for a significant percentage of morbid-
PREVENTION AND TREATMENT OF ity and mortality during the first 100 days after
ACUTE GRAFT-VERSUS-HOST DISEASE
transplant [37]. Pretransplant evaluation with
Prevention of acute graft-versus-host disease baseline pulmonary function tests, including mea-
consists primarily of immunosuppression after the surement of diffusion capacity, is mandatory. Poor
infusion of allogeneic stem cells in an attempt to pulmonary function is a relative contraindication
decrease T-cell activation and proliferation. The to transplant.
most commonly used prophylactic drugs include
cyclosporine, tacrolimus, methotrexate, and cor- EARLY COMPLICATIONS
ticosteroids in varying combinations. The ideal Early pulmonary complications, occurring
prophylactic regimen has yet to be determined. within the first 100 days of transplant, include
Treatment of acute graft-versus-host disease pulmonary edema, bacterial infections (eg, S
consists of continuing the original immunosup- pneumoniae and Gram-negative infections), Pneu-
pressive prophylaxis and adding glucocorticoids mocystis infections, and fungal infections with
at moderate-to-high doses. Treatment regimens Aspergillus and Candida. However, viral infections
vary depending on the patient or institution, but are the greatest threat during the first 3 months.
standard approaches entail prompt use of methyl- Etiologic agents include herpes simplex virus, re-
prednisolone at 1–2 mg/kg/day, tapering when spiratory syncytial virus, and CMV. CMV infec-
symptoms improve. The overall response rate to tion resulting from reactivation of late and en-
steroids in acute graft-versus-host disease is 50%– dogenous virus is responsible for about half of the
80% [33]. For steroid-resistant graft-versus-host cases of interstitial pneumonia. It usually occurs
disease, several therapies have been tried, with 6–12 weeks after hematopoietic stem cell trans-
variable success, including sirolimus (Rapamune), plant and has a high mortality, even with therapy.
mycophenolate mofetil (CellCept), antithymo- Early diagnosis of CMV pneumonia is critical be-
cyte globulin (Thymoglobulin), photophoresis, cause prompt institution of ganciclovir and high-
psoralen with ultraviolet A (PUVA) therapy, and dose immunoglobulin therapy is associated with
monoclonal antibodies to different cytokines, such improved survival [38].
as the interleukin-2 receptor and tumor necrosis Idiopathic pneumonia syndrome (IPS) is de-
factor [34]. Unfortunately, steroid-resistant acute fined as diffuse lung injury after hematopoietic
230 www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGYstem cell transplant, for which an infectious etiol- poietic stem cell transplant defined a reduced
ogy has not been identified [39]. Histologically, pretransplant FEV1 (forced expiratory volume Pallera
an interstitial mononuclear infiltrate is associated at 1 second) of < 80% of predicted and graft- Schwartzberg
with diffuse alveolar damage. About 10% of allo- versus-host disease prophylaxis with cyclosporine
geneic transplant recipients develop IPS, whereas and/or methotrexate as factors that predicted an
it is much less common in autologous stem cell increased risk of severe pulmonary complications
transplant. Risk factors include graft-versus-host [42]. T-cell–depleted transplants were associated
disease, poor performance status, and high-dose with a lower risk of complications. Factors that
total body irradiation. The diagnosis of IPS is one were not associated with development of severe
of exclusion. The following criteria have been pro- pulmonary complications included grades 2–4
posed as a definition of IPS by the National Heart, acute graft-versus-host disease, tobacco use, age
Lung and Blood Institute: signs and symptoms of > 50 years, sex, unrelated donor, CMV serologic
pneumonia, abnormal pulmonary physiology, dif- status, disease status at transplantation, pre-
fuse alveolar damage with multilobar infiltrates, transplant carbon monoxide diffusing capacity,
and an absence of active lower respiratory tract and total body irradiation. Patients receiving an
infection. There is no specific therapy for IPS, al- autologous transplant had a significantly lower
though corticosteroids are often used. incidence of pulmonary problems than patients
Diffuse alveolar hemorrhage, a form of idio- receiving allogeneic transplants.
pathic pneumonia syndrome, is characterized by
multilobular culture-negative lung injury, with in- LATE COMPLICATIONS
creasingly bloody samples during bronchoalveolar Late pulmonary complications (ie, those oc-
lavage, indicating alveolar hemorrhage [40]. The curring 100+ days after transplant) include both
complication occurs most frequently at the time infectious etiologies and noninfectious causes.
of engraftment, about 2 weeks after hematopoi- Viral infections, such as herpes zoster and CMV
etic stem cell transplant, and is seen in both au- infections, may occur while immunosuppressive
tologous and allogeneic transplant patients. Risk therapy is being given. Occasionally, idiopathic
factors include older age at transplant, total body pneumonia syndrome may occur 3 months or
irradiation, severe mucositis, solid malignancy, re- more after transplant [43]. Chronic graft-versus-
nal insufficiency, and white-blood-cell recovery. host disease may directly or indirectly affect the
Early diagnosis is mandatory because high doses of lungs. Sinopulmonary infections, sicca syndrome
corticosteroids, typically 500–1,000 mg of methyl- with chronic bronchitis, progressive obstructive
prednisolone in divided doses for 5 days, followed airway disease, chronic aspiration, and late-onset
by a slow taper in dosage, improve survival and lymphoid interstitial pneumonia may occur in as-
decrease the chance of subsequent respiratory sociation with chronic graft-versus-host disease.
failure [41]. Bronchiolitis obliterans is a not-infrequent late
complication of allogeneic transplant and some-
DIAGNOSTIC WORKUP times, though rarely, of autologous transplant. Ini-
Stem cell transplant patients with pulmonary tially, symptoms are those of upper respiratory in-
symptoms require a prompt, aggressive diagnostic fection. Many patients develop gradual worsening
evaluation. The workup should include imaging of pulmonary function tests, with irreversible air-
studies with a chest x-ray and/or high-resolution flow obstruction, air trapping, and reduced diffus-
computed tomography (CT) chest scan, pulmo- ing capacity. Subsequently, dyspnea with cough,
nary function tests, and sputum culture with di- expiratory wheezes, and hyperinflation develop.
rect fluorescent antibody (DFA). Bronchoscopy The diagnosis can often be made with characteris-
with bronchoalveolar lavage, including a cell tic pulmonary function tests, bronchoscopy, bron-
count, culture, DFA assay, and cytology, is an im- choscopy with lavage, and transbronchial biopsy.
portant tool in investigating pulmonary infiltrates. Occasionally, open lung biopsy is required. Treat-
Occasionally, transbronchial biopsy, CT-guided ment, including use of high-dose corticosteroids,
needle aspiration biopsy, or open lung biopsy will has been disappointing.
be required. In general, patients studied with pulmonary
A recent review of prognostic factors for early function tests after hematopoietic stem cell trans-
severe pulmonary complications after hemato- plant occasionally have a variety of abnormalities,
VOLUME 2, NUMBER 3 ■ MAY/JUNE 2004 www.SupportiveOncology.net 231etic stem cell transplant should undergo a cardiac
Table 5 evaluation, although effective screening strategies
Pulmonary Complications of Hematopoietic are not well established. In general, patients with
Stem Cell Transplant pretreatment reduction in left ventricular ejection
TYPE OF TRANSPLANTa fraction (LVEF) below the lower limit of normal or
TYPE DISEASE AUTOLOGOUS ALLOGENEIC antecedent moderate-to-severe cardiac symptoms
Infections Bacterial +++ +++ are excluded from transplant. Historic factors that
Fungal ++ +++ predict transplant-related cardiac dysfunction in-
Pneumocystis carinii ++ +++ clude chest irradiation, prior anthracycline use,
Cytomegalovirus ± +++ and reduced LVEF.
Other viruses + +++ The incidence of moderate-to-severe cardiac
Other Pulmonary edema +++ +++ dysfunction requiring treatment in the immediate
Diffuse alveolar hemorrhage ± ++ post-transplant period ranges from 0% to approxi-
Idiopathic pneumonia syndrome + +++ mately 10%, with the variability likely explained
Bronchiolitis obliterans + +++ by differing regimens and patient populations.
Impaired pulmonary function tests ++ +++ Severe or fatal congestive heart failure typically
Graft-versus-host disease ± +++ occurs early in the peri-transplant or immediate
a
Incidence of complications: +++ = common; ++ = less common; + = rare; ± = exceedingly rare post-transplant period. Treatment is identical to
Adapted from Soubani et al [36]
that used for other causes of left ventricular dys-
function and/or pericarditis/pericardial effusion.
including airflow obstruction, restriction pattern, The late effects of transplantation on myocar-
Hematopoietic and decreased diffusion capacity. A 2002 review dial function have been evaluated, most common-
Stem Cell [44] demonstrated an average 18% DLCO drop ly in children. In general, there does not appear to
in 83% of allogeneic transplant patients, with be an increase in late cardiac dysfunction, even
Transplant
gradual improvement over time. Total lung capac- when subclinically determined by LVEF mea-
ity declined by an average of 16% by 9 months surement in survivors of hematopoietic stem cell
after transplant, with 12% recovery by 32 months. transplant up to 10 years after the event [46, 47].
Although 23% of patients developed a persistent
obstructive pattern on pulmonary function tests, Renal Toxicity
the absolute magnitude of the FEV1/FVC (forced Nephrotoxicity in the setting of a hematopoi-
vital capacity) ratio was only 3%, unlikely to be sig- etic stem cell transplant is commonly multifacto-
nificant. The most common predisposing factor to rial. For example, renal insufficiency can occur
pulmonary function abnormalities occurring late as a consequence of the use of multiple drugs
after hematopoietic stem cell transplant is chronic throughout the transplant course. Acute tubular
graft-versus-host disease. Table 5 summarizes the necrosis can be caused by nephrotoxins such as
relative incidence of pulmonary complications in aminoglycosides, amphotericin B, contrast media,
autologous and allogeneic hematopoietic stem or chemotherapy agents used in the preparative
cell transplant patients. regimen, such as ifosfamide or cisplatin. Acute
nephrotoxicity occasionally occurs secondary to
Cardiac Toxicity cell-lysis products from a prior preserved stem cell
Certain drugs common to high-dose chemo- collection. Often, sepsis is associated with renal
therapy regimens, most notably cyclophospha- insufficiency. Severe renal toxicity requiring he-
mide, can occasionally cause cardiac toxicity. modialysis rarely occurs, but mortality in bone
Cyclophosphamide typically induces pericarditis marrow transplant recipients requiring hemodial-
with congestive heart failure. Other drugs used in ysis is high (up to 80%) [48]. Additionally, acute
hematopoietic stem cell transplant, including cy- interstitial nephritis may be caused by sulfur com-
tarabine, busulfan (Busulfex, Myleran), ifosfamide pounds, cimetidine, methicillin, or other drugs.
(Ifex), and thiotepa, also have the potential to
cause cardiomyopathy [45]. Occasional acute TREATMENT
cardiac effects are also seen with the reinfusion of Treatment of a transplant patient with renal
bone marrow itself. toxicity starts with a careful review of the patient’s
Virtually all patients referred for hematopoi- medical history. The medication record should be
232 www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGYscrutinized for nephrotoxic medicines and diag- tion and doses ranging from 8 to 14 Gy; in many
nostic agents (such as contrast dye for CT scans). aspects, it resembles radiation nephritis. Histo- Pallera
Serial observation of electrolytes is very important logically, a renal biopsy in a patient with BMT Schwartzberg
to managing renal complications. An early rise in nephropathy shows mesangiolysis and changes in
the serum creatinine level should alert the physi- the glomerular basement membrane and overlying
cian regarding the continued use of nephrotoxic endothelium. Treatment consists of careful con-
agents. Significant electrolyte wasting can occur. trol of blood pressure, with some studies suggest-
Early intervention with appropriate supple- ing that angiotensin-converting enzyme inhibitors
mentation maintains normal levels of potassium, may provide additional renal protection [50].
magnesium, and phosphorus. Diligent monitor-
ing of a patient’s weight and his or her fluid status HEMORRHAGIC CYSTITIS
during the transplant process is also important, Hemorrhagic cystitis occurs in up to 70% of
and the appropriate use of diuretics or intrave- patients following high-dose chemotherapy and
nous fluids can prevent significant dehydration or stem cell transplant without any prophylaxis and
fluid overload. Renal toxicity has also been linked in 5%–35% of patients who receive prophylaxis
to immunosuppressants, such as cyclosporine or [51]. This complication most commonly occurs
tacrolimus, used to prevent or treat graft-versus- following treatment with high-dose ifosfamide or
host disease. Monitoring of cyclosporine and cyclophosphamide, but other drugs (such as busul-
tacrolimus levels is necessary to prevent renal tox- fan and etoposide), irradiation, and some viruses
icity from drugs such as amphotericin B, foscarnet, (such as BK polyomavirus, CMV, or adenovirus)
and ganciclovir. can also cause this problem. Hematuria may oc-
Glomerular diseases typically develop as a re- cur at any time—from within hours following the
sult of the underlying malignancy, rather than the administration of these drugs to up to 3 months
transplant per se. The most common of these dis- following treatment—but the peak incidence of
orders is minimal-change disease with Hodgkin’s hemorrhagic cystitis is within days of chemother-
lymphoma, membranous nephropathy with non- apy administration.
Hodgkin’s lymphoma, membranoproliferative glo- Monitoring daily urinalysis is mandatory dur-
merulonephritis associated with cryoglobulinemia ing preparative regimens containing high doses
in chronic lymphocytic leukemia, and amyloidosis. of cyclophosphamide or ifosfamide. Prophylactic
Significant proteinuria should alert the physician measures are required, including hyperhydration
to the possibility of these underlying disorders. to achieve > 3 L of urine output per day and the
Usually, the transplant should proceed to treat use of mesna (Mesnex) to bind the acrolein me-
the malignancy, adding immunosuppressives to tabolite of these drugs, which then protects the
control the glomerular disease. bladder epithelium. For treatment of mild hemor-
Drugs such as cyclosporine or mitomycin C rhagic cystitis, aggressive hydration, diuresis, blad-
have been associated with TTP/hemolytic ure- der antispasmodics, and close follow-up of blood
mic syndrome (HUS). This spectrum of disorders counts and serum chemistries are the mainstay of
should be entertained when renal insufficiency is therapy. For macroscopic hematuria with clots and
encountered in association with microangiopathic significant bladder pain, bladder irrigation with
hemolytic anemia, thrombocytopenia, fever, or water, saline, or alum should be used, along with
changes in mental status. When this diagnosis appropriate analgesics. For unresponsive cases, re-
is confirmed, the offending agent, such as cyclo- ferral to a urologist for cystoscopy and the possible
sporine, should be discontinued immediately and instillation of formalin should be considered.
plasmapheresis with plasma exchange should be
instituted. Neurologic Toxicity
A rare disorder termed bone marrow trans- Several neurologic disorders or problems can
plant (BMT) nephropathy is characterized by pro- affect the stem cell recipient, but the most com-
gressive renal insufficiency (usually seen within mon complication affecting the central nervous
the first year after transplantation), proteinuria, system is encephalopathy. In many instances, a
microscopic hematuria, hypertension, and anemia correlation between when the neurologic event
[49]. BMT nephropathy has been linked to pre- occurred and the stage of the transplant can direct
parative regimens that include total body irradia- the physician to an etiology. For example, seizures
VOLUME 2, NUMBER 3 ■ MAY/JUNE 2004 www.SupportiveOncology.net 233enous ammonia load with increased ammonium
Hematopoietic Table 6 excretion by hemodialysis.
Stem Cell Drugs Used in Bone Marrow Transplant Many drugs used as part of the transplant pro-
That Can Cause Encephalopathya cess can cause seizures and/or encephalopathy [54].
Transplant
Some of the more common ones are listed in Table
Antineoplastic agents Antimicrobial agents 6. For example, high-dose busulfan, a chemothera-
Cytarabine Penicillins*
Ifosfamide Cephalosporins*
peutic agent used in many different preparative reg-
Paclitaxel Aminoglycosides* imens, can cause seizures in up to 10% of patients
Mechlorethamine Isoniazid* who are not given antiepileptics. Prophylactic treat-
Cisplatin Metronidazole* ment with phenytoin is now routinely employed
Methotrexate Rifampin*
5-Fluorouracil Antiviral agents
when busulfan is used. Cyclosporine and tacrolimus
Procarbazine Acyclovir are common causes of encephalopathy, seizures, and
Immunosuppressive agents Ganciclovir hypertension in the stem cell transplant recipient.
Cyclosporine Miscellaneous Close monitoring of drug levels and careful man-
Tacrolimus Benzodiazepines
Muromonab Narcotics* agement of blood pressure, using antihypertensive
Antifungal agents Anesthetics agents as needed, are crucial to prevent complica-
Amphotericin B Antiepileptics tions from these immunosuppressants.
a
Renal or hepatic dysfunction and hypoalbuminemia may alter the phar-
macokinetics and pharmacodynamics of many of these drugs, resulting in HEMATOMAS
neurotoxicity at lower than expected doses. Drugs marked with an asterisk
(*) may also cause seizures. For patients with focal neurological deficits,
Adapted from Krouwer [54] MRI is very important to rule out a hemorrhagic
lesion. Subdural hematomas have also been report-
prior to stem cell infusion are frequently caused by ed, with an incidence ranging from 2.6% in clini-
the preparative regimen, whereas those occurring cal series to 12% in autopsy series of hematopoi-
during the first few weeks after an hematopoietic etic stem cell transplant patients [55]. Frequently,
stem cell transplant are typically caused by im- the focal neurological deficits are bilateral and
munosuppressive drugs, such as cyclosporine or associated with thrombocytopenia, coagulopathy,
tacrolimus. Seizures occurring after that point are a pretransplant lumbar puncture for intrathecal
due to infections or cerebrovascular events. methotrexate, and the presence of a headache fol-
For encephalopathic stem cell recipients, lowing lumbar puncture. Management is usually
magnetic resonance imaging (MRI) of the brain conservative, unless neurologic deterioration oc-
should be performed to rule out a significant hem- curs in association with an increase in the size of
orrhagic event, a new or recurrent malignant le- the subdural hematoma.
sion, or an infection. For normal or nonspecific Intracranial hematomas have a more complex
MRI results, the differential diagnosis for changes set of causes, including an association with Asper-
in mental status includes malignant hypertension, gillus infection, cerebral venous sinus thromboses,
significant electrolyte or acid-base disturbances, and cyclosporine toxicity. Mortality is high, as this
hypoxia, infection, TTP/HUS, hepatic renal insuf- complication often appears in a relapsed patient
ficiency, and drug-induced etiologies. Wernicke’s with end-stage disease.
encephalopathy (the triad of altered mental sta- Cerebrovascular events also have been reported
tus, ophthalmoplegia, and ataxia) has also been in the hematopoietic stem cell transplant recipient
reported in autologous and allogeneic hematopoi- [56]. Nonbacterial thrombotic endocarditis has been
etic stem cell transplant patients [52]. implicated as a cause of embolic infarctions in trans-
A rare, but nearly always fatal, neurologic com- plant patients. Physicians should be cognizant of this
plication in hematopoietic stem cell transplant association when a cerebrovascular accident occurs
patients called idiopathic hyperammonemia is in the setting of a transplant and consider evaluation
characterized by the acute onset of lethargy, with transesophageal echocardiography.
confusion, tachypnea, and vomiting [53]. Rapid
progression to coma and death usually follows. INFECTIONS
Objectively, elevated plasma ammonia levels Several infections that can cause meningoen-
(> 70 µmol/L) and respiratory alkalosis are seen. cephalitis can occur in the post-transplant set-
Treatment involves reduction of a patient’s exog- ting. Agents that can cause significant central
234 www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGYnervous system infections include bacterial in- myalgias, and arthralgias, in conjunction with
fections (eg, Streptococcus, Listeria, or Nocardia), elevated creatinine phosphokinase levels. Differ- Pallera
fungal infections (eg, Aspergillus, Zygomycetes, or entiation from steroid myopathy is important be- Schwartzberg
Candida), viral infections (eg, herpes zoster, ad- cause the therapy for each is markedly different.
enovirus, VZV, human herpes virus 6, and the JC Electromyography to differentiate between the
virus), and protozoal infections (eg, toxoplasma). two and, occasionally, a muscle biopsy are impor-
Symptoms may be classic for meningitis, but, tant diagnostic tests.
alternatively, there may be a paucity of symp- Myasthenia gravis is a rare and late complica-
toms—perhaps only fever and headache—be- tion after allogeneic hematopoietic stem cell trans-
cause of the immunocompromised condition of plant, usually developing between 2 and 5 years
these patients. Further, the lack of an adequate after transplantation. Myasthenia gravis occurs
immune response may not only blunt symptoms in the setting of chronic graft-versus-host disease
but may also minimize abnormalities on examina- and tapering immunosuppression [58]. Thymomas
tion of the cerebral spinal fluid or imaging studies. are not usually associated with posthematopoietic
Examination of the cerebral spinal fluid with PCR stem cell transplant myasthenia gravis. Anti-
has been found to be very useful in determining acetylcholine receptor antibodies may or may not
an occult infectious process when culture data be present. Treatment for myasthenia gravis con-
are inconclusive. sists of corticosteroids and pyridostigmine, with
generally good responses. Recently, rituximab was
PERIPHERAL NERVOUS SYSTEM found to have some benefit in this disorder and is
Observation for neurologic complications af- another therapeutic option [59].
fecting the peripheral nervous system is also im-
portant. Polyneuropathies, typically affecting the Conclusion
distal extremities in the setting of hematopoietic Hematopoietic stem cell transplant is associat-
stem cell transplant, are usually associated with ed with significant toxicity and side effects, which
chemotherapeutic drugs such as cisplatin or the fortunately are becoming increasingly manageable.
taxanes. These symptoms are slowly reversible Both autologous and allogeneic transplant recipi-
with discontinuation of the offending agent. Poly- ents are at risk for infections related to immune
neuropathies may also prompt a search for a para- compromise. Allogeneic hematopoietic stem cell
neoplastic neurologic syndrome. transplant recipients have the additional burden
Guillain-Barré syndrome–like disorders can of graft-versus-host disease, which influences mul-
occur, but with a low incidence in hematopoietic tiple organ toxicities. Attention to prophylaxis,
stem cell transplant patients [57]. Clinical signs prompt detection, and early aggressive interven-
include progressive ascending motor weakness, tion for specific side effects of hematopoietic stem
dysesthesias, muscle cramps, and an inability to cell transplant result in an improved outcome, in-
bear weight. Treatment consists of plasmapher- creasing the benefit of this rigorous but beneficial
esis, intravenous immune globulin, or corticoste- treatment approach.
roids, with variable responses. Peer viewpoints on this
Polymyositis may develop in 0.5%–3% of allo- article by Drs. Thomas
geneic transplant patients and is associated with Acknowledgments: The authors thank Beth Coul- C. Shea and Stephen
chronic graft-versus-host disease. The polymyosi- ter for her expert assistance with the preparation of J. Forman appear on
tis is characterized by proximal muscle weakness, the manuscript. pages 237 and 241.
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