American Society of Clinical Oncology guidelines state that the use of the
neurokinin receptor-1 antagonist, aprepitant, should be considered, although evidence
to support its use in HCT patients is lacking.
102 Because aprepitant is a moderate
inhibitor of cytochrome P-450 3A4, it may theoretically interact with the preparative
regimen, especially cyclophosphamide. Well-controlled studies evaluating its
efficacy, along with its potential for causing drug interactions, are needed.
data suggest that the serotonin antagonist ondansetron may increase
cyclophosphamide clearance in patients undergoing a myeloablative HCT.
However, further work is needed to identify the clinical implications of this finding
because, to date, cyclophosphamide concentrations have not been consistently
associated with clinical outcomes in patients undergoing a myeloablative HCT.
Most patients receiving a myeloablative preparative regimen may also experience
mucositis due to its effects on rapidly dividing cells of the oral epithelium. The use
of methotrexate as GVHD prophylaxis also contributes to mucositis.
mucositis may also contribute to the development of nausea and anorexia.
In severe cases, parenteral opioid analgesics for pain relief
nutrition (TPN) may be needed. Because mucositis can be worsened by
superinfection, good oral hygiene should be practiced. Soft toothbrushes should be
107 Oral mucositis can be decreased with the use of
recombinant human keratinocyte growth factor palifermin. The Multinational
Association of Supportive Care in Cancer and International Society for Oral
Oncology Guidelines recommend palifermin to prevent mucositis for patients with
hematologic malignancies receiving myeloablative chemotherapy and TBI with
autologous HCT. Palifermin 60 mcg/kg/day is given for 3 days immediately prior to
administering the preparative regimen and for 3 days after infusion of the
hematopoietic stem cell graft (i.e., days 0, +1, +2).
lowered the incidence and average duration of clinically meaningful oral mucositis.
The incidence of blood-borne infections and the use of parenteral opioids were also
diminished in patients using palifermin.
Myelosuppression and Growth Factor Use
until the ANC has recovered to 500/μL for 2 consecutive days. Is this therapy appropriate for K.M.?
The use of hematopoietic growth factors after infusion of allogeneic PBPC is
controversial and is not recommended by ASCO Guidelines.
hematopoietic growth factors after allogeneic graft infusion decreases the duration of
neutropenia, but has not been demonstrated to decrease cost, length of hospitalization,
or antibiotic use. Hematopoietic growth factor administration may increase the
incidence of severe GVHD and lower survival.
109 K.M. is receiving an allogeneic
PBPC graft and thus should not receive filgrastim.
Sinusoidal Obstructive Syndrome (SOS)/VenoOcclusive Disease of the Liver
weight is 85 kg. Laboratory values on day +7 are significant for the following:
Aspartate aminotransferase (AST), 40 units/L
Alkaline phosphatase, 120 units/L
until day +18 when they reach the following peak values:
Alkaline phosphatase, 180 units/L
Sinusoidal obstructive syndrome (SOS), formerly known as VOD, is a syndrome
consisting of fluid retention, right upper quadrant pain, and hyperbilirubinemia. In
severe cases, it results in renal failure, encephalopathy, multiorgan failure, and
ultimately may result in death. The incidence of SOS/VOD varies depending on the
definition used to diagnose the syndrome; however, it is most commonly associated
with high-dose chemotherapy with HCT. It has been reported to occur in 5% to 55%
of patients undergoing myeloablative HCT.
110,111 The major risk factor for the
development of SOS/VOD is high-dose chemotherapy associated with myeloablative
transplants. Preparative regimens including busulfan, cyclophosphamide, and/or TBI
greater than 13.2 Gy have been associated with higher SOS/VOD rates.
19,112 Patientspecific factors such as older age, impaired performance status, and advanced
disease have also been reported to increase SOS/VOD risk.
Although the exact pathophysiology underlying the development of SOS/VOD is
not fully understood, it is known that damage to the sinusoidal endothelial cells in the
liver is the initial insult which initiates the process. Damage continues and leads to
sloughing of the endothelial lining of the sinusoids ultimately resulting in embolism
and obstruction of sinusoidal flow.
113 This obstruction of flow within the liver
contributes to postsinusoidal portal hypertension and worsening liver dysfunction,
usually manifested by increased bilirubin and ascites.
CLINICAL PRESENTATION AND DIAGNOSIS
CASE 101-3, QUESTION 8: What signs and symptoms in K.M. are consistent with a diagnosis of
The initial signs and symptoms of SOS/VOD can occur anytime within the first 15
to 30 days post-transplant. Insidious weight gain exceeding 5% of baseline may be
one of the first manifestations of impending SOS/VOD, occurring in more than 90%
of patients within 3 to 6 days after marrow infusion.
sodium and water retention, as evidenced by decreased renal sodium excretion. New
onset of transfusion refractory thrombocytopenia may also be an early sign of
impending SOS/VOD. Hyperbilirubinemia, which also occurs in virtually all
patients, follows the onset of weight gain and usually appears within 10 days after
hematopoietic stem cell infusion. Other liver function test abnormalities usually
occur after hyperbilirubinemia and include elevations in AST and alkaline
phosphatase. Ascites, right upper quadrant pain, and encephalopathy lag behind
changes in liver function tests and develop within 10 to 15 days after infusion of
Although liver biopsy is the gold standard for diagnosis of SOS/VOD, its use is
limited due to the risk of bleeding during the procedure. Other noninvasive criteria
have been developed to help diagnosis SOS/VOD after HCT. Two sets of clinical
criteria call for an evaluation of hyperbilirubinemia, ascites/weight gain, and right
upper quadrant pain not attributable to other causes such as medications, acute
111,114 Along with these criteria, ultrasound may be useful in
determining whether there is reversed hepatic venous flow and to confirm ascites
CASE 101-3, QUESTION 9: What is the likelihood that K.M. will recover from her SOS/VOD? How should
There is no standard treatment for SOS/VOD although many patients with
SOS/VOD (70%–85%) spontaneously recover. Preventive measures look to control
patient risk factors, and pharmacologic prevention strategies have also been used.
Patient-specific risk factors are often not reversible; however, selection of
preparative regimens such as nonmyeloablative regimens, avoidance of
concomitant hepatotoxic drugs, use of fractionated TBI, and the use of adaptive
busulfan dosing may reduce risk. Preventive medications have also been
investigated. The use of prophylactic heparin has shown varied results in clinical
trials; therefore, its use is still controversial.
ursodeoxycholic acid are also inconclusive. However, some trials have shown a
benefit in reducing the incidence of SOS/VOD with its use. According to one trial,
patients who received ursodeoxycholic acid were shown to have decreased
hepatotoxicity, less acute GVHD, and better survival.
Other treatments consist of supportive-care measures such as management of
sodium and water balance, and paracentesis, in severe cases, for ascites that is
associated with pain and pulmonary compromise.
albumin and colloids may be used to maintain intravascular volume, spironolactone
may be used to minimize extravascular fluid accumulation, and protein restriction and
lactulose may be used if encephalopathy develops. Unfortunately, improved
outcomes with these measures have not been confirmed. In patients with severe
SOS/VOD and multiorgan failure, available treatment options are limited.
Thrombolytic therapy with recombinant human tissue plasminogen activator and
heparin have had mixed results in terms of efficacy and can cause fatal intracerebral
105 Defibrotide, an investigational drug, has shown promising
results in the treatment of SOS/VOD.
117–119 Defibrotide, a ribonucleotide, has
antithrombotic, anti-ischemic, and thrombolytic activity without producing significant
systemic anticoagulation. In a compassionate use trial of 88 patients with severe
SOS/VOD and associated organ dysfunction, 36% of patients had complete
resolution of SOS/VOD and 35% survived past day 100 after HCT.
Although the use of defibrotide in treating SOS/VOD appears to be effective, little
is known about whether prophylactic defibrotide could be beneficial in high-risk
patients. Corbacioglu et al. explored this question in children with malignant infantile
osteopetrosis undergoing stem cell transplantation. Previously 7/11 or 63.6% (n =
20) of the children in their center between 1996 and 2001 experienced SOS/VOD.
Defibrotide prophylaxis was initiated in nine consecutive patients between 2001 and
2005 and in this group 1/9 (11.1%) was diagnosed with moderate SOS/VOD,
suggesting a significant benefit from prophylactic defibrotide. To further explore this
question, a US National Institutes of Health-sponsored prospective randomized trial
has been undertaken to answer the question as to whether prophylactic defibrotide is
superior to therapeutic defibrotide in children at high risk for experiencing
SOS/VOD during stem cell transplantation.
Because K.M. does not meet the criteria for severe SOS/VOD, she should be
managed conservatively with fluid restriction and spironolactone for fluid diuresis.
Her signs and symptoms should resolve during the next 2 weeks. Because she has
mild SOS/VOD, she is likely to recover completely without sequelae.
preparative regimen is as follows: fludarabine 30 mg/m
/day on days −4, −3 and −2 and 2 Gy TBI on the day of
Differential, no granulocytes or monocytes detected
Donor T-cell chimerism is <5%. What is E.R. experiencing and how should she be treated?
Reduced-intensity regimens typically consist of fludarabine in combination with an
alkylating agent or low-dose TBI (Fig. 101-3). With the nonmyeloablative
fludarabine/TBI regimen, there is minimal neutropenia, thrombocytopenia, and other
2 Engraftment is usually evident within the first 30 days in
patients receiving a nonmyeloablative preparative regimen; however, rejection can
occur after initial engraftment.
121 Mixed chimerism, a state where both host and donor
cells coexist, generally develops after nonmyeloablative HCT. E.R. has low donor
T-cell chimerism on day +28, placing her at high risk of graft rejection.
Graft rejection occurs particularly after nonmyeloablative allogeneic HCT. A
delicate balance exists between host and donor effector cells. This is established
with myelosuppressive chemotherapy and immunosuppressants to decrease the risk
of excessive host-versus-graft effects that could lead to graft rejection. The incidence
of graft rejection is higher in patients with aplastic anemia and in patients undergoing
HCT with histoincompatible marrow or T-cell-depleted marrow. There are limited
therapeutic options for the treatment of graft rejection. A second HCT is the most
definitive therapy, assuming donor cells are available, although the toxicities are
In patients receiving myeloablative allogeneic HCT, graft rejection is
best managed with immunosuppressants such as ATG. In patients receiving a
reduced-intensity regimen, graft rejection may require a second HCT.
E.R. received nonmyeloablative conditioning, and thus, she should have mixed
chimerism post-transplant; however, she has fewer than 5% donor T cells. Current
research is focusing on quantitative chimerism monitoring, specifically evaluating the
percent donor chimerism, which may be used as a tool with which to base clinical
80 Donor chimerism is evaluated in different cell types (e.g., T cells,
NK cells, granulocytes) although the cell type most predictive of outcome is not
known. The changes in the percent donor chimerism over time post-transplant, termed
“engraftment kinetics,” are influenced by several factors such as type of HCT
conditioning, stem cell source, and intensity of postgrafting immunosuppression.
A balance between the recipient’s and donor’s cells is needed to maximize the GVT
effect, which lowers the risk of relapse while minimizing the risk of GVHD.
Based on E.R.’s state of chimerism, she will not benefit from the GVT effect due to
the lack of the donor’s cytotoxic T lymphocytes that suppress the recipient’s
E.R. is at high risk of graft rejection and therefore may not benefit from the
transplant. A trial of discontinuing cyclosporine and mycophenolate mofetil, in an
attempt to shift the balance toward donor graft growth and away from recipient T-cell
growth, is an option. E.R.’s T-cell chimerism should be monitored periodically and
hematopoietic function should be monitored with daily CBC and a bone marrow
biopsy as clinically indicated.
Graft-versus-host disease is caused by activation of donor lymphocytes, leading to
immune-mediated damage to the recipient. Histocompatibility differences between
donor and recipient necessitate post-transplantation immunosuppression after
allogeneic HCT because considerable morbidity and mortality are associated with
graft rejection and GVHD. Therefore, immunosuppression or GVHD prophylaxis is
used after allogeneic HCT. However, because allogeneic transplantation offers the
potential for a GVT effect in which immune effector cells from the donor recognize
and eliminate residual tumor in the recipient, research is focusing on immune
suppression manipulations that allow sufficient GVT effects while not increasing the
risk of graft rejection and GVHD.
TBI, total body irradiation; THY, thymoglobulin. *TBI >1,200 cGy;
‡3.2 to 16 mg/kg; §90 to 250 mg/m
Leukemia. 2006;20:1701, with permission.)
Graft-versus-host disease is the most important complication of allogeneic HCT
and limits the use of this lifesaving treatment in patients without histocompatible
2,125 GVHD can occur after allogeneic HCT, regardless of the preparative
regimen used. The pathophysiology of GVHD is not completely understood, but the
current view of its development is described by a three-step process, including (a)
the preparative regimen causing tissue damage and release of inflammatory cytokines
into the circulation; (b) recipient and donor antigen presenting cells and inflammatory
cytokines triggering activation of donor-derived T cells; and (c) activated donor T
cells mediating cytotoxicity through a variety of mechanisms, which leads to tissue
damage characteristic of acute GVHD (aGVHD).
Graft-versus-host disease has traditionally been divided into two forms (i.e., acute
or chronic) based on time points and clinical manifestations. Acute GVHD, defined
as occurring during the first 100 days post-transplant, damages the skin, GI tract, and
In contrast, chronic GVHD (cGVHD) may affect almost any organ system,
closely resembles several autoimmune diseases, and occurs after day 100. With the
introduction of nonmyeloablative HCT, the time course of GVHD has shifted and a
late-onset aGVHD occurring after day 100 is possible; however, in these individuals,
acute and chronic GVHD symptoms may both be present. As such, consensus criteria
developed by The National Institutes of Health have classified GVHD based on
clinical manifestations and not time after HCT.
The majority of the data regarding the prevention and treatment of GVHD have
been obtained after myeloablative preparative regimens. Therefore, the subsequent
section refers only to trials conducted in recipients of a myeloablative allogeneic
Acute Graft-versus-Host Disease
QUESTION 1: M.P., a 22-year-old, 70-kg man, undergoes a one-antigen mismatched allogeneic HCT from
his sister for the diagnosis of Philadelphia chromosome-positive (Ph
) AML. After a myeloablative preparative
2 on days +3, +6, and +11. What factors are
associated with an increased risk of acute GVHD?
The single most important factor associated with the development of GVHD is the
degree of histocompatibility between donor and recipient.
II–IV acute GVHD occurs in 20% to 50% of HLA-matched sibling grafts and 50% to
80% of HLA-mismatched sibling or HLA-identical unrelated donors.
aGVHD is earlier and severity is increased in mismatched grafts relative to matched
grafts, and also in MUDs relative to matched sibling donors.
increase the risk of experiencing aGVHD include increasing recipient (and possibly
donor) age, greater intensity of the preparative regimen, use of PBPC rather than
bone marrow, and donor/recipient sex mismatch.
126 Umbilical cord transplants have a
M.P. is receiving allogeneic bone marrow from a female sibling donor that is
mismatched at one HLA antigen. These two factors increase his risk of exhibiting
aGVHD. Therefore good immunosuppressive therapy is critical in preventing its
The primary targets of immune-mediated destruction of host tissue by donor
lymphocytes in aGVHD are the skin followed by the GI tract (diarrhea) and the
128,133 Acute GVHD of the skin, the most common site of aGVHD, usually
manifests as a diffuse maculopapular, pruritic rash that starts on the palms of the
hands, soles of the feet, or the face. In more severe cases, skin aGVHD can progress
to a generalized total body erythroderma, bullous formation, and skin desquamation.
The earliest symptoms of aGVHD of the GI tract are usually loss of appetite
followed by nausea and vomiting.
105 Abdominal pain and watery or bloody diarrhea
also occur, which can result in electrolyte abnormalities, dehydration, or ileus in
severe cases. Liver GVHD usually follows skin and/or GI GVHD. Clinical
symptoms of liver GVHD include a gradual rise in total bilirubin, alkaline
phosphatase, and hepatic transaminases.
105 Acute GVHD is usually not evident until
the time of engraftment, when donor lymphoid elements begin to proliferate. The skin
is usually the first organ to be involved. The onset of liver or GI GVHD usually lags
behind the onset of skin GVHD by approximately 1 week and infrequently occurs
Modified Glucksberg Grading of Acute Graft-versus-Host Disease
500–1,000 mL/day diarrhea or biopsyproven upper GI involvement
Bilirubin 3–6 mg/dL 1,000–1,500 mL/day diarrhea
3 Maculopapular rash >50% body
4 Generalized erythroderma with
Bilirubin >15 mg/dL >2,000 mL/day diarrhea or severe
abdominal pain with or without ileus
aExtent of rash determined by “rule of nines.”
bDiarrhea volume applies to adults.
eds. Thomas’ Hematopoietic Cell Transplantation. 4th ed. Malden, MA: Blackwell; 2009:1291.
Acute GVHD must be distinguished accurately from other causes of skin, liver, or
GI toxicity in the HCT patient. For example, a maculopapular rash, which may occur
as a manifestation of an allergic reaction to antibiotics, usually begins on the trunk or
upper extremities and is rarely present on the palms of the hands or soles of the feet.
Diarrhea can be caused by chemotherapy, radiation, infection, or antibiotic
105 However, diarrhea caused by the preparative regimen is rarely bloody
and usually resolves within 3 to 7 days after discontinuation of drugs and radiation.
Diarrhea caused by infectious agents such as Clostridium difficile or
cytomegalovirus (CMV) should be distinguished from GVHD. Liver GVHD must be
distinguished primarily from SOS/VOD and, to a lesser extent, hepatitis induced by
drugs, blood products, or parenteral nutrition. Although liver function test
abnormalities between these syndromes are similar, liver GVHD is rarely associated
with insidious weight gain or right upper quadrant pain.
affected organ in conjunction with clinical evidence is the only way to definitively
diagnose aGVHD, though biopsy of the gut or liver is rarely done due to the
increased risks associated with thrombocytopenia early in the post-transplant phase.
Acute GVHD is associated with characteristic histologic changes to affected organs.
A staging system based on clinical criteria is used to grade aGVHD. The severity of
organ involvement is determined first (Table 101-6), and then an overall grade is
established based on number and extent of involved organs (Table 101-7).
Modified Glucksberg versus International Bone Marrow Transplant Registry
Overall Grading of Acute Graft-versus-Host Disease Severity
II—Moderate Stage 3 or Stage 1 or Stage 1
III—Severe Stage 2–3 or Stage 2–4
IV—Life-threatening Stage 4 or Stage 4 —
B—Moderate Stage 2 Stage 1 or 2 Stage 1 or 2
C—Severe Stage 3 Stage 3 Stage 3
D—Life-threatening Stage 4 Stage 4 Stage 4
eds. Thomas’ Hematopoietic Cell Transplantation. 4th ed. Malden, MA: Blackwell; 2009:1291.
IBMTR, International Blood and Marrow Transplant Registry.
M.P. developed a rash at the time of engraftment that could have been consistent
with either an antibiotic-induced rash or aGVHD. Although it was appropriate to
change antibiotics, the fact that M.P.’s rash did not improve is suggestive of aGVHD.
M.P.’s rash is present on 36% of his body, but because there are no signs of GI or
liver involvement at this time, M.P. is likely to have grade I aGVHD (Tables 101-6
CASE 101-5, QUESTION 3: Why did M.P. receive prophylactic immunosuppressive therapy with
cyclosporine and methotrexate?
Graft-versus-host disease is a leading cause of morbidity and mortality after
allogeneic HCT. Without immunosuppression, serious aGVHD would occur in
almost every allogeneic HCT recipient.
2 The most common method used to minimize
GVHD risk is to administer prophylactic immunosuppressive therapies and most
patients receive multi-drug GVHD prophylaxis.
Historically, aGVHD was prevented with single-drug therapy using ATG,
cyclophosphamide, methotrexate, or cyclosporine.
134–136 ATG binds nonspecifically
to mononuclear cells and depletes hematopoietic progenitor cells in addition to
lymphocytes. Consequently, ATG is generally avoided as a prophylactic agent due to
134 The risk of GVHD is greatly reduced by two-drug
combination immunosuppression (Table 101-8). Although the most widely published
regimen is short-course methotrexate plus cyclosporine,
regard to the most effective regimen. Several randomized clinical trials have
86 Recipients of matched sibling grafts treated
with tacrolimus had a lower incidence of grade II to IV aGVHD but a similar
137 Overall survival was lower in the tacrolimus group as a
result of more toxic deaths in patients with advanced stage disease; however, a
higher number of advanced stage disease patients in the tacrolimus/methotrexate
group make the results of this trial somewhat difficult to interpret.
then taper 5% per week and discontinue by day +180
Tacrolimus/short term Tacrolimus 0.03 mg/kg/d continuous IV infusion or 0.12 mg/kg/d PO
3.75 mg/kg IV until day +35; then 7 mg/kg/d (Neoral) PO, dose adjusted
to cyclosporine concentrations (via radioimmunoassay) of 200–400
ng/mL. Taper by 20% every 2 weeks; then discontinue by day +180
Methylprednisolone 0.5 mg/kg/day IV day +7 until day +14; then 1
mg/kg/d IV until day +28; then prednisone 0.8 mg/kg/day PO until day
+42; then taper slowly and discontinue by day +180
BID, twice a day; IV, intravenous; PO, orally.
Subsequently, the International Blood and Marrow Transplant Registry conducted
a matched control study, which suggested that the survival difference between the
In patients receiving HLA-matched or slightly mismatched unrelated grafts, those
given tacrolimus had a lower incidence of grade II to IV aGVHD, a similar incidence
of cGVHD, and similar disease-free and overall survival rates.
currently used in allogeneic HCT after myeloablative preparative regimens.
More recently, the use of mycophenolate mofetil has been studied in allogeneic
transplants with myeloablative conditioning used in combination with cyclosporine.
It appears to have a similar incidence of aGVHD and 100-day survival as
methotrexate/cyclosporine, yet significantly less severe mucositis and more rapid
neutrophil engraftment than the methotrexate/cyclosporine arm.
mofetil is now commonly used in clinical practice in combination with cyclosporine
M.P. received acute GVHD prophylaxis with a two-drug regimen of short-course
methotrexate and cyclosporine, the most common regimen for myeloablative
allogeneic conditioning regimens. Using two drugs with different mechanisms of
immunosuppression, one blocking the activation of T cells (cyclosporine) and the
other (methotrexate) blocking the division and clonal expansion of activated T cells,
is more effective in decreasing the likelihood of GVHD than one of these agents
CASE 101-5, QUESTION 4: What principles are used in dosing medications used for acute GVHD
Although the various combination immunosuppressive regimens vary slightly by
drug, dose, and combination, several guidelines are consistent throughout all
regimens. First, methotrexate used for prophylaxis of aGVHD is withheld or given in
reduced doses if mucositis is severe or the patient experiences excessive fluid
136,141 Fluid retention sites act as a depot for methotrexate accumulation,
increasing duration of exposure. Methotrexate for GVHD prophylaxis can delay
engraftment, increase the incidence and severity of mucositis, and cause liver
function test elevations. The methotrexate dose is reduced in the setting of renal or
The calcineurin inhibitors (i.e., cyclosporine, tacrolimus) should be initiated
before or immediately after donor cell infusion (day −3 to 0) when used for GVHD
prophylaxis. This schedule is recommended because of the known mechanism of
action of these agents, which entails blocking the proliferation of cytotoxic T cells by
inhibiting production of helper T-cell-derived interleukin-2 (IL-2). Administering
cyclosporine before the donor cell infusion allows inhibition of IL-2 secretion to
occur before a rejection response has been initiated.
Cyclosporine is usually administered intravenously until the GI toxicity from a
myeloablative preparative regimen has resolved (e.g., for 7–21 days).
because GI effects of the preparative regimen (e.g., chemotherapy-induced nausea
and vomiting, diarrhea) and GVHD affect the oral absorption of microemulsion
cyclosporine and may result in inconsistent blood concentrations.
the microemulsion oral formulation (Neoral) or other new generic microemulsion
formulations that have improved bioavailability. With the microemulsion oral
formulation, an IV to PO dosing ratio of 1:2 or 1:3 is appropriate. The most common
ratio used when converting tacrolimus from IV to oral is 1:4. Empiric dose
adjustments may be required when patients are receiving concomitant medications
(e.g., voriconazole) that affect cytochrome CYP3A4 or P-glycoprotein, which are
involved in the metabolism and transport of the calcineurin inhibitors. Thus, careful
monitoring for drug interactions with the calcineurin inhibitors is warranted.
The dose of cyclosporine or tacrolimus is adjusted based on serum drug levels and
the serum creatinine (SCr) concentration. Although the calcineurin inhibitors do not
contribute to myelosuppression, common adverse effects to these agents include
electrolyte abnormalities, neurotoxicity, hypertension, and/or nephrotoxicity.
Tapering schedules for GVHD prophylaxis vary widely among institutions. The
general goal is to keep calcineurin inhibitor
doses stable until day +50 and then slowly taper with the intent of discontinuing all
immunosuppressive agents by 6 months after HCT. By this time, immunologic
tolerance has developed, and patients no longer require immunosuppressive therapy.
This can only be accomplished if the patient is not experiencing GVHD.
ADAPTIVE DOSING OF CALCINEURIN INHIBITORS
The role of pharmacokinetic monitoring of the calcineurin inhibitors in HCT
patients is not well defined but is commonly performed because of the established
pharmacodynamic associations within solid organ transplant recipients. It is standard
practice for HCT centers to adjust cyclosporine or tacrolimus doses based on trough
145 An association between cyclosporine concentrations and
aGVHD was not found in early studies; however, other studies have suggested that
cyclosporine trough concentrations for 12-hour dosing of 200 to 400 ng/mL in adult
patients minimize the risk of aGVHD and the risk of cyclosporine-induced
146–148 For continuously infused cyclosporine, higher target blood
concentrations of 300 to 500 ng/mL have been required to prevent GVHD in order to
provide an equivalent AUC of exposure to intermittent dosing.
note that cyclosporine-induced nephrotoxicity may occur despite low or normal
recent studies suggest that trough concentrations do not correlate well with exposure
to cyclosporine and that a peak level is better correlated to the AUC(0–12). A peak
concentration of greater than 800 ng/mL may be required to prevent GVHD. Despite
this, the data are limited and the routine use of peaks for therapeutic drug monitoring
151 Desired tacrolimus trough concentrations are 5 to 15 ng/mL.
Tacrolimus concentrations greater than 20 ng/mL have been associated with
increased risk of toxicity, primarily nephrotoxicity.
145,152 Adjustments in tacrolimus
dosing for increased SCr should be made in a manner similar to that described for
It is reasonable to adjust M.P.’s doses to maintain cyclosporine trough
concentrations between 200 and 400 ng/mL, as in all patients undergoing allogeneic
HCT with a myeloablative preparative regimen. Recommendations for dose
adjustments should be based on cyclosporine concentrations and SCr level. No
standard dosage adjustment schedule exists, but most centers adopt their own
standardized approach. M.P. has a normal SCr, and his cyclosporine trough is 392
ng/mL. Therefore, his cyclosporine dose should be maintained and the trough
repeated in a few days. It may be repeated sooner if an interacting drug is added or
discontinued, or if there are toxicity concerns.
TREATMENT OF ESTABLISHED ACUTE GRAFT-VERSUS-HOST
CASE 101-5, QUESTION 6: In the third week post-transplant, M.P. experiences a pruritic rash on his
of acute skin GVHD is confirmed by biopsy. On the same day, M.P. develops diarrhea (1,000 mL over 24
hours. What is the rationale for methylprednisolone therapy in M.P.?
Preventing the development of aGVHD is the most effective way to treat this HCT
complication. In patients who develop aGVHD, first-line treatment is a
corticosteroid added to their current immune suppression regimen.
aGVHD and its treatment cause profound immunodeficiency.
aGVHD and infectious complications is the leading cause of mortality for allogeneic
The route of corticosteroid administration is determined by the severity of the
aGVHD. Those patients with only skin involvement of less than 50% of their body
surface area may be treated with topical steroid creams, whereas involvement of
other organs, or stage 3 or 4 skin disease, requires systemic corticosteroids. A
complete response occurs in up to 25% to 40% of patients, with a lower likelihood
of response in more severe cases of aGVHD.
126,153 Patients with mild-to-moderate
(grades I–III) aGVHD who respond to initial therapy have a significantly better
survival advantage than patients with severe aGVHD who do not respond to initial
therapy. Patients who do not respond to corticosteroid therapy or have ongoing
severe GVHD usually die from a combination of GVHD and infectious
Corticosteroids used in the treatment of aGVHD are generally tapered based on
response. There is no consensus on the optimal method for tapering the
153 and the tapering rate depends on the patient. Patients who
experience aGVHD or who experience flares of existing GVHD during a tapering
trial will have their dosages increased or tapered more slowly as tolerated.
Because M.P. had objective evidence of established aGVHD, he was given
systemic IV corticosteroids. This was appropriate because single-agent
corticosteroids are considered the therapy of choice for established aGVHD.
Corticosteroids indirectly halt the progression of immune-mediated destruction of
host tissues by blocking macrophage-derived interleukin-1 secretion. Interleukin-1 is
a primary stimulus for helper T-cell-induced secretion of IL-2, which in turn is
responsible for stimulating proliferation of cytotoxic T lymphocytes. The
recommended dosage of methylprednisolone for the treatment of established aGVHD
is 1 to 2 mg/kg/day, given intravenously or orally in divided doses, followed by a
tapering schedule that is determined by response.
154,155 Trials that compared higher
doses of corticosteroids (i.e., 10 mg/kg/day) to 2 mg/kg/day as initial treatment of
156 Monitoring for rash, diarrhea, and bilirubin levels
to asses aGVHD response should occur daily.
126 M.P. was receiving cyclosporine for
GVHD prophylaxis at the time the aGVHD developed. Although the cyclosporine
was not effective in preventing the aGVHD, it is typical for patients to remain on
their prophylactic immune suppressants.
A significant portion of patients do not respond to corticosteroids, and they are
said to have steroid-refractory GVHD.
If aGVHD symptoms worsen during 3 days
of treatment and if the skin does not improve by 5 days, it is unlikely that a response
will be achieved in a timely manner, and secondary therapy should be considered.
Patients with steroid-refractory aGVHD have a poorer prognosis. A variety of
medications are being studied for “salvage” or secondary therapy. The salvage
therapy depends on the organs affected. For example, phototherapy is used as salvage
therapy for skin GVHD, and nonabsorbable corticosteroids are used for GI GVHD.
Other options for salvage therapy include ATG, denileukin diftitox, and TNF-α
blockers (e.g., infliximab, etanercept).
126,157 The most effective dose, timing, or
combination of these salvage therapies is still unknown.
M.P. should be evaluated for response to methylprednisolone after 4 to 7 days. If
his aGVHD has improved or stabilized, he should be continued on therapy at this
dose for a total of 14 days. If M.P. responds to therapy, his methylprednisolone dose
should be tapered slowly over a minimum of 1 month, and he should be monitored for
any evidence of recurrent GVHD. If the GVHD
flares during his steroid taper as evidenced by worsening skin reactions, increased
bilirubin, or increased diarrhea volume, the dose should be increased again until his
disease is stable; the subsequent taper should be initiated at a slower rate. If M.P.
fails to respond to first-line therapy with methylprednisolone, he should receive
Chronic Graft-versus-Host Disease
CASE 101-5, QUESTION 7: M.P. was successfully treated for his aGVHD, is no longer taking
concentration. What is the most likely cause of M.P.’s findings?
Chronic GVHD (cGVHD), the most common late complication of allogeneic HCT,
occurs in 20% to 70% of patients surviving more than 100 days.
a major cause of nonrelapse morbidity and mortality.
include recipient, donor, and transplant factors. Nonmodifiable recipient risk factors
include older age, certain diagnoses (e.g., CML), and lack of an HLA-matched donor.
Modifiable factors that may lower the risk of cGVHD include selecting a younger
donor, avoiding a multiparous female donor, using umbilical cord blood or a bone
marrow graft rather than PBPC, and limiting the CD34
Development of aGVHD is a major predictor of cGVHD; 70% to 80% of those with
grade II to IV aGVHD go on to develop cGVHD.
Chronic GVHD is not a continuation of aGVHD. Traditionally, the boundary
between the two was based on time, but now they are classified based on different
158 Signs and symptoms of cGVHD in various organ systems are
A consensus guideline for the diagnosis and scoring of cGVHD has been
127 The diagnosis of cGVHD requires (a) being distinct from aGVHD, (b)
having at least one diagnostic clinical sign of cGVHD or at least one distinctive
manifestation confirmed by pertinent biopsy or other relevant tests, and (c) exclusion
of other possible diagnoses. The clinical scoring system uses a numerical value of 0
to 3, with more severe symptoms having a higher number. A global score is
calculated by including the number of organs involved and the severity within each
affected organ. The global score reflects the expected effect of cGVHD on the
patient’s performance status and can be used to evaluate whether treatment with
systemic immunosuppression is required. The grading and prognosis of cGVHD can
define and predict high-risk patient groups.
Selected Signs and Symptoms of Chronic Graft-versus-Host Disease
Affected Organ Diagnostic Distinctive Other Features
Gastrointestinal tract Esophageal web Pancreatic
Skin Poikiloderma Depigmentation Seat impairment
Keratosis pilaris Maculopapular rash
Sclerotic features Hypopigmentation
genitalia; muscles, fascia, and joints; and other organs, are also described by Filipovich et al.
aPart of chronic GVHD symptomatology if the diagnosis is confirmed.
bDiagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes).
Infection, drug effects, malignancy, or other causes must be excluded.
GVHD, graft-versus-host disease.
The signs and symptoms of cGVHD in M.P. include a rash in sun-exposed areas of
the skin, hyperpigmentation of tissues surrounding his eyes, white plaque-like lesions
in the mouth, dry mucous membranes, and increased alkaline phosphatase and total
bilirubin levels. These symptoms appeared after a period of complete resolution of
aGVHD and during a taper of the cyclosporine. Thus, M.P. has moderateinvolvement, quiescent cGVHD.
rational? What other agents are available to treat cGVHD?
There is no specific prophylactic therapy for cGVHD, and the optimal treatment
remains controversial. The mainstay of therapy for cGVHD is long-term
immunosuppressive therapy. Survival for patients with cGVHD is improved by
extended corticosteroid therapy, although there are multiple long-term adverse effects
associated with the corticosteroids.
158,160 A typical regimen is prednisone 1
mg/kg/day, administered orally in divided doses for 14 days and then converted
160 Alternateday therapy is preferred to minimize adrenocortical suppression. Once therapy is
initiated, 1 to 2 months may pass before an improvement in clinical symptoms is
noted. Therapy is usually continued for 9 to 12 months and then slowly tapered after
signs and symptoms of cGVHD have resolved. The median duration of treatment has
been reported to be 23 months.
If cGVHD worsens during the tapering or after
discontinuation of prednisone, immunosuppressive therapy is restarted. Other
potential approaches for patients with refractory cGVHD include mycophenolate
mofetil, daclizumab, sirolimus, pentostatin, and extracorporeal photophoresis.
When immunosuppressive therapy is administered for long periods, the patient
must be monitored closely for chronic toxicity. Cushingoid effects, aseptic necrosis
of the joints, and diabetes can develop with long-term corticosteroid use. Other
severe complications include a high incidence of infection with encapsulated
organisms and atypical pathogens such as Pneumocystis jiroveci (P. jiroveci)
pneumonia, CMV, and herpes zoster.
It is reasonable to start M.P. on single-agent prednisone for cGVHD treatment at 1
mg/kg daily for 2 weeks and then convert to every other day as described.
Patients who are being treated for cGVHD should receive trimethoprim–
sulfamethoxazole for prophylaxis of P. jiroveci and encapsulated organisms, such as
Streptococcus pneumoniae and Haemophilus influenzae. Ensuring optimal
prophylactic antibiotics in cGVHD patients is critical because infection is the
primary cause of death during treatment.
161 Artificial tears and saliva may improve
lubrication and decrease the occurrence of cracking and fissures in mucous
membranes. Newer therapies such as cyclosporine ophthalmic emulsion and
autologous serum tears have provided relief for chronic ocular GVHD.
nutritional intake is poor, consultation with a clinical nutritionist and use of oral
nutritional supplementation may be advisable. Patients should be instructed to apply
sunscreens to exposed areas whenever prolonged sun exposure is anticipated. Liver
function abnormalities have been improved by up to 30% with the use of ursodiol as
bile acid displacement therapy.
163–165 Calcium supplements, estrogen replacement, or
other anti-osteoporosis agents should be considered in women or other patients at
risk for fracture or bone loss while receiving prolonged regimens with
166 Patient education regarding the gradual resolution of
symptoms such as skin sclerosis, fatigue and muscle weakness, anticipated duration
of therapy, and importance of compliance with oral immunosuppressive therapy is
Opportunistic infections are a major cause of morbidity and mortality after
myeloablative and nonmyeloablative HCT. There are three general periods of
infectious risk (Fig. 101-2). During the early period pre-engraftment, particularly for
patients undergoing myeloablative HCT, the primary pathogens are aerobic bacteria,
Candida spp., and herpes simplex virus (HSV). Chemotherapy-induced mucosal
damage creates a portal of entry into the bloodstream for many organisms, such as
viridans group Streptococcus, Candida, and aerobic gram-negative bacteria.
Catheter-associated infections have become the leading cause of bacteremia, most
notably in the early post-transplant period.
159,161 The routine use of antiviral
prophylaxis has decreased the incidence of HSV. Respiratory viruses such as
respiratory syncytial virus (RSV), influenza, adenovirus, and parainfluenza are
increasingly recognized as pathogens causing pneumonia, particularly during
community outbreaks of infection.
167 To reduce potential exposure of HCT recipients
to these pathogens, visitors and staff members with signs and symptoms of a viral
respiratory illness may not be allowed direct contact with patients.
A potential advantage of reduced-intensity or nonmyeloablative preparative
regimens is reduced toxicity of the preparative regimen compared to myeloablative
HCT. Reduced-intensity or nonmyeloablative preparative regimens frequently do not
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