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366 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 367

TABLE 23–3. Complications of Hematopoietic Cell chimerism is less than 5 percent at any point after reduced-intensity
allogeneic HCT. Donor T-cell chimerism levels greater than 5 percent
Transplantation
but less than 95 percent are generally termed “mixed chimerism,” while
Vascular access complications full donor chimerism is defined by blood donor T-cell chimerism of
Graft failure 95 percent or greater.
Blood group incompatibilities and hemolytic complications
Acute GVHD Incidence of Graft Failure
Chronic GVHD The incidence of graft failure varies widely in published reports. To esti-
mate the incidence of graft failure following autologous HCT, consider
Infectious complications that in most centers the TRM associated with autologous HCT is less
Bacterial infections than 5 percent, of which only a small subset can be attributed to graft
Fungal infections failure. Another surrogate marker for estimating the incidence of graft
Cytomegalovirus infection failure following autologous HCT is the requirement for hematopoietic
Herpes simplex virus infections cell rescue using a backup autograft product. A study of 300 patients
Varicella-zoster virus infections who underwent autologous HCT revealed that 4.7 percent required
294
their backup product. Thus, it is reasonable to estimate that the inci-
Epstein-Barr virus infections dence of graft failure following autologous HCT is somewhere between
Adenovirus, respiratory viruses, HHV-6, -7, -8, and other viruses 1 and 5 percent.
Gastrointestinal complications Graft failure following allogeneic HCT is more complex, because of
Mucosal ulceration/bleeding confounding factors such as histocompatibility, ABO matching, graft-
Nutritional support versus-host and host-versus-graft reactions, and the use of postgrafting
immunosuppression. The overall incidence of graft failure after alloge-
Hepatic complications neic HCT is approximately 5 to 6 percent. In general, graft failure is
295
Sinusoidal obstructive syndrome uncommon after high-dose conditioning and in patients who are heav-
Hepatitis: infectious versus noninfectious ily pretreated with cytotoxic chemotherapy before coming to allogeneic
Lung injury HCT. Even in the myeloablative setting, though, the incidence of graft
Interstitial pneumonitis: infectious versus noninfectious failure varies with conditioning regimen, as illustrated in a randomized
Diffuse alveolar hemorrhage trial where graft failure occurred in zero of 64 (0 percent) of patients
receiving BU/CY but in five of 62 (8 percent) of patients receiving BU/
Engraftment syndrome FLU. The risk of graft rejection is highest in patients who are heavily
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Bronchiolitis obliterans presensitized or who have autoimmunity directed at hematopoietic cells
Kidney and bladder complications (as in aplastic anemia), those who receive low CD34+ cell doses, 295,296
Endocrine complications and those with diseases such as myelofibrosis where the marrow micro-
Drug–drug interactions environment is significantly perturbed.
The consequences of graft failure, and its optimal treatment,
Growth and development depend in large part upon the likelihood of autologous hematopoietic
Late onset nonmalignant complications recovery. In patients who have received high-dose conditioning, autolo-
Osteoporosis/osteopenia, avascular necrosis, dental prob- gous marrow recovery is likely to be severely delayed if not absent, and
lems, cataracts, chronic fatigue, psychosocial effects, and graft failure is associated with high mortality rates as a consequence of
rehabilitation prolonged cytopenias. Second-salvage allogeneic HCT has been used
Secondary malignancies successfully to treat graft failure in this setting; reported outcomes vary
Neurologic complications from dismal to encouraging, 297,298 and likely depend substantially on
Infectious, transplant conditioning and immune suppression patient selection. There is no consensus on whether to use the same
medication toxicities or a different donor for salvage allogeneic HCT for graft rejection, and
the decision often depends on donor availability. The time needed to
GVHD, graft-versus-host disease; HHV, human herpes virus subtypes. identify and collect a second allograft product are often prohibitive for
patients with graft rejection and pancytopenia, and thus readily avail-
able HSC sources such as UCB and HLA-haploidentical family mem-
the inability to detect a meaningful percentage (usually >5 percent) of bers have sometimes been used.
donor hematopoietic elements. In contrast, poor graft function describes For patients with graft failure after RIC, autologous hematopoietic
the failure to achieve adequate blood counts following allogeneic HCT recovery is more likely. For these patients, the optimal strategy often
in the presence of substantive donor hematopoietic cell chimerism. involves withdrawing postgrafting immunosuppression and awaiting
autologous count recovery. However, for patients with malignant dis-
Graft Failure Following Reduced-Intensity Conditioning ease, the risk of relapse is substantially elevated in the setting of graft
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Allogeneic HCT following RIC is associated with incomplete eradica- failure, presumably as a result of a loss of GVT effects.
tion of host hematopoiesis. As a consequence, a significant percentage
of patients have mixed donor/host hematopoietic chimerism for sev-
eral months after transplantation before converting to complete donor REGIMEN-RELATED ORGAN TOXICITIES
type. 186,293 Primary engraftment following reduced-intensity allogeneic The severity of organ toxicities associated with HCT is a function of the
HCT is defined by neutrophil, platelet, and hemoglobin count recovery intensity of conditioning therapy, the amount of prior therapy received,
as outlined above as well as stable donor T-cell chimerism. As described patient comorbidities before transplantation, and posttransplantation
above, graft failure is said to have occurred when blood donor T-cell factors such as immunosuppressive medication and antimicrobial agents.

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