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CHAPTER 94: Hematopoietic Stem Cell Transplantation and Graft-Versus-Host Disease 883

its inherent risks for infection. Often narcotic analgesics are needed for
TABLE 94-2 Drugs Used in Conditioning a
pain management—compounding the issues of nausea and producing
Busulfan—alkylating agent Hepatotoxicity, mucositis, seizures, darkening of the somnolence. In addition to their marrow suppressive effects, many of
skin, cataracts the agents used for conditioning in the allogeneic transplant setting
Carmustine—alkylating agent Infusion pain and burning of the face, hepatotoxicity, are also lymphocytotoxic—producing immunosuppression, and thus
nausea, vomiting, hypotension, pulmonary fibrosis expanding the spectrum of pathogens to which the patient is susceptible
(see the section “Infectious Complications”).
Cyclophosphamide—alkylating Electrolyte imbalances, cardiomyopathy, SIADH,
agent nausea, vomiting, diarrhea, hemorrhagic cystitis In the case of autologous HSCT, the conditioning includes only the
high-dose chemotherapy, radiotherapy, and/or monoclonal antibody
Cytosine arabinoside— Nausea, vomiting, diarrhea, neurotoxicity, ocular irrita- therapy, and does not require immunosuppression. As a consequence,
antimetabolite tion, capillary leak syndrome, hand-foot syndrome the complications are due to the direct toxic effect of this therapy
Etoposide—topoisomerase II Infusion hypotension/hypertension, acidosis during and the resulting cytopenias.
inhibitor infusion, nausea, vomiting, diarrhea, rash, mucositis Additional agents that may be used during the conditioning in allo-
Fludarabine—antimetabolite Nausea, vomiting, fever, immunosuppression geneic HSCT include antithymocyte globulin and immunosuppressive
medications used to prevent GVHD and graft rejection (Table 94-2). The
Ifosfamide—alkylating agent Nephrotoxicity, neurotoxicity, acidosis during infusion
primary activity of these agents is lymphocytotoxic— suppressing both
Melphalan—alkylating agent Cardiac, nausea, vomiting, diarrhea, mucositis, renal the patient’s immune system to prevent rejection of the transplanted
dysfunction graft and the transplanted immune system provided by the donor. This
Thiotepa—alkylating agent Hand-foot syndrome, nausea, vomiting, diarrhea, immunosuppressive effect results in the patient becoming more sus-
mucositis, mental status changes, and psychosis ceptible to opportunistic pathogens such as viruses and Pneumocystis
jiroveci (see the section “Infectious Complications”).
Rituximab—monoclonal anti- Infusion reactions, suppression of B-cell function and
body against CD19 hypogammaglobulinemia, cytopenias, reactivation of
hepatitis B and other viral infection, progressive multi- GRAFT-VERSUS-HOST DISEASE
focal leukoencephalopathy, mucocutaneous reactions
Graft-versus-host disease (GVHD) remains the most important com-
Immunosuppressive drugs plication of allogeneic HSCT. This clinicopathologic syndrome is an
Alemtuzumab Anaphylactic reaction, hypotension, fever, rigors, immunologic reaction of donor lymphocytes to “foreign” antigens
reactivation, and susceptibility to viral infections present on the surface of host cells. The most important proteins are
HLAs encoded by the major histocompatibility complex but differences
Antithymocyte globulin Anaphylactic or infusion reactions, hypotension, fever, in “minor” antigens, not currently tested in donor selection, are targets
rigors, rash, reactivation of viral infections
for both GVHD and graft-versus-leukemia. The requirements for a
Cyclosporine Nephrotoxic, hypertension, neurotoxicity, diagnosis of GVHD defined by Billingham 50 years ago remain valid
immunosuppressive today: (1) the graft must contain immunocompetent cells; (2) the host
Mycophenolate mofetil Nausea, vomiting, diarrhea, bone marrow suppression, must express tissue antigens that are not present in the transplant donor,
immunosuppressive and (3) the host must be incapable of mounting an effective response
to eliminate the transplanted cells. While historically the classification
15
Sirolimus Hyperlipidemia, cytopenias, thrombotic microangiopathy, of GVHD was based on timing (acute—occurring within 100 days after
hepatotoxicity, pulmonary toxicity, immunosuppressive
HSCT and chronic—occurring after 100 days), the current consensus is
Tacrolimus Nephrotoxic, hypertension, neurotoxicity, that this distinction be made by clinical manifestations rather than time
immunosuppressive from transplantation alone. In addition to acute and chronic GVHD,
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a All of these drugs can cause myelosuppression. the National Institutes of Health (NIH) classification includes late-onset
acute GVHD (after day 100) and an overlap syndrome with features of
toxicity being myelosuppression. As would be expected drug dosing does both acute and chronic diseases. 17
bone marrow resulting in myelosuppression and peripheral blood cyto- ■ GVHD PROPHYLAXIS
impact on the severity of these toxicities. Sites of greatest effect are the
penias, and the oropharynx and gastrointestinal (GI) tract manifested as Although histocompatibility matching is critical in limiting the inci-
oral and intestinal mucositis, pain, and diarrhea. The direct toxic effects dence and severity of acute GVHD, this alone cannot prevent it. Almost
to mucosa are most often caused by the alkylating agents. Side effects on all recipients of unmodified allogeneic HSCT develop GVHD if not
other organs are less common and vary between agents. given posttransplant immunosuppression. The primary pharmacologi-
The dose of total body irradiation varies widely when used as condi- cal strategy to prevent GVHD is inhibition of calcineurin, a cytoplasmic
tioning for HSCT. Fractionating the doses tends to reduce the toxicities. enzyme important for activation of T cells. The calcineurin inhibitors,
Doses less than 900 cGy are considered nonmyeloablative but as the cyclosporin and tacrolimus, have similar mechanisms of action, clinical
dose is escalated, the incidence of GI complications such as nausea, effectiveness, and toxicity. The most serious side effects of calcineurin
vomiting, diarrhea, and mucositis will increase. Furthermore, the higher inhibitors include renal insufficiency, thrombotic microangiopathy
the total dose of radiation used, the more significant the impact on the manifesting as severe cytopenias, and posterior reversible encepha-
bone marrow and the peripheral blood counts. In the nonmyeloablative lopathy syndrome presenting with seizures. Calcineurin inhibitors
transplants, often only one dose of total body irradiation (200 cGy) is are usually administered in combination with other agents such as
administered for its immunosuppressive effect. This dose produces little methotrexate or less toxic, mycophenolate mofetil. Sirolimus is an
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in the way of systemic side effects except possibly some nausea. immunosuppressive agent that is structurally similar to tacrolimus but
The marrow suppression produced by high doses of chemotherapy is not a calcineurin inhibitor. It has been used in combination with
and radiotherapy used for myeloablative HSCT results in peripheral tacrolimus. 19,20 In addition to pharmacologic approaches, removal of
blood cytopenias, increasing the risk of infection, bleeding, and the need donor T lymphocytes from the stem cell inoculum either in vitro or in
for transfusions. The development of mucositis and the loss of normal vivo has been effective in preventing GVHD. Currently, strategies of
barriers to pathogens in the oral cavity and GI tract compound the risk T-cell depletion include negative selection of T cells ex vivo, positive
of infection generated by the cytopenias alone. If oral nutrition cannot selection of CD34+stem cells ex vivo, and use of antibodies against
be maintained, patients will need total parental nutrition (TPN) with T cells in vivo and ex vivo. 21

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