Page 1893 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 109 Complications After Hematopoietic Cell Transplantation 1675

morphology on culture or histopathology or on tests to detect fungal establish autologous engraftment. This is accomplished by infusing
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components or nucleic acids. Nasal and bronchial washings for approximately 1 × 10 autologous marrow mononuclear cells/kg.
Aspergillus also may not be sensitive and lung biopsy may be required Most investigators recommend infusion of a minimum of at least 2
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to obtain a definitive diagnosis. The galactomannan assay is an × 10 marrow mononuclear cells/kg to ensure establishment of an
enzyme-linked immunosorbent assay to detect the Aspergillus cell wall allogeneic graft. UCB derived hematopoietic grafts can engraft with
glycoprotein; it has a high specificity, but low sensitivity for diagnos- a lower number of cells. Stem cells and progenitors can be damaged
ing invasive aspergillosis and has not been reproducible in well- by cryopreservation or by ex vivo purging, and additional cells are
designed trials. Similarly, testing for β-D-glucan has modest clinical required if intensive purging, especially with alkylators, is performed
utility, but low sensitivity. Molecular methods for diagnosis, includ- though currently this approach to autograft preparation is uncom-
ing PCR for Aspergillus DNA, are also undergoing development. mon. Selection of CD34+ cells as a technique for tumor cell depletion
More invasive evaluations (e.g., fine needle aspiration or biopsy) are does not compromise engraftment, unless the quantitative cell losses
often needed to confirm the presence of Aspergillus in suspicious through selection are excessive.
lesions identified on clinical exam or imaging studies. The use of hematopoietic stem cells and progenitors harvested
The use of high-efficiency air filters has reduced the nosocomial from the blood by apheresis instead of the bone marrow has become
acquisition of Aspergillus, at least during the early neutropenic phase widely prevalent, both for autologous and allogeneic HCT. Autolo-
when isolation measures are used. The optimal pharmacologic strat- gous peripheral blood hematopoietic cell grafts (PBSC) are collected
egy for primary prophylaxis against aspergillosis in HCT recipients after mobilization of marrow-derived progenitors into the blood by
is not well defined. Posaconazole has been shown to be effective for cytokine (G-CSF or GM-CSF) therapy or during recovery from
prophylaxis in HCT recipients with GVHD. A large randomized trial myelosuppressive chemotherapy, often in combination with growth
showed no difference in fungal-free survival between voriconazole factors (Chapter 97). Progenitor content of blood or marrow grafts
and fluconazole in HCT recipients at low risk for disease progression is assayed by quantitation of mononuclear cells expressing the hema-
or early HCT mortality, although there was a trend towards fewer topoietic progenitor-associated surface marker CD34. Peripheral
Aspergillus infections and less empiric antifungal use in voriconazole graft mobilization can be further enriched by the use of plerixafor,
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recipients. Inhaled or low dose intravenous amphotericin has not an inhibitor of CXC-chemokine receptor 4 that releases cells from
been effective for primary prophylaxis. In patients with a previous the marrow. Allogeneic grafts are mobilized from healthy donors
history of invasive aspergillosis, secondary prophylaxis with a mold- using growth factors alone, nearly exclusively using G-CSF though
specific azole (e.g., oral voriconazole or posaconazole) or parenteral clinical trials with plerixafor are ongoing.
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echinocandins or an amphotericin preparation is recommended, Graft failure is uncommon if >2 × 10 CD34+ cells/kg or more
possibly for the duration of intensive immunosuppression. Therapy are collected, cryopreserved, and later infused as an autologous graft
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with a mold-specific azole, an echinocandin, or an amphotericin though guidelines often target >5 × 10 /kg for prompt neutrophil
preparation should be initiated in patients with invasive aspergillosis and platelet recovery. The minimum CD34 content for an allogeneic
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or in high-risk patients with persistent febrile neutropenia. Azoles graft is less well defined, but more than 5 × 10 CD34+ cells/kg is
and echinocandins have a more favorable side effect profile compared frequently cited as a target collection for an allogeneic donor allograft.
with amphotericin formulations. Patients with disease progressing on Mobilized PBSC grafts yield satisfactory and more rapid trilineage
a single antimold drug might need combination therapy with two hematopoietic recovery than grafts from marrow-derived cells. Similar
antimold agents. The role of adjunctive measures such as cytokine to marrow grafting, late graft failure is possible, but unlikely (<5%)
growth factors, immunoglobulin infusion, or granulocyte transfusion after transplantation using PBSC. Infusion of a sufficient graft cell
remains undefined. dose (nucleated or CD34+ cells) may be the most important control-
Other molds including fusarium, alternaria or the zygomycetes lable factor to limit the risk of graft failure.
may present similarly and might be difficult to distinguish on tissue Recipient myelofibrosis or splenomegaly can interfere with
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biopsy. Aggressive antifungal therapy is required for their manage- engraftment. Splenomegaly can delay hematologic recovery, presum-
ment and may require multidrug therapy. Granulocyte transfusions ably because both progenitors and mature blood cells are sequestered
may be an important adjunct for treatment of invasive fungal infec- in the spleen and may particularly prolong dependence on platelet
tions during neutropenia, but formal studies have not demonstrated transfusions. The presence of moderate severe myelofibrosis also
improvements in survival. 20,21 delays engraftment, perhaps because of faulty homing of stem cells
in the marrow microenvironment.
Posttransplantation therapy can jeopardize engraftment. Graft
EARLY NONINFECTIOUS COMPLICATIONS failure or poor graft function has been associated with use of metho-
trexate, ATG, acyclovir, ganciclovir, trimethoprim-sulfamethoxazole
High-dose chemotherapy and radiation regimens are used before (TMP-SMX), and mycophenolate mofetil (MMF). Posttransplant
transplantation for their antineoplastic and immunosuppressive complications such as CMV, HHV-6 or fungal infections, and acute
effects. However, these treatments can damage host tissue, resulting and chronic GVHD can also compromise successful engraftment.
in significant morbidity. Early HCT-associated complications can Allogeneic HCT, especially using unrelated or mismatched
frequently simulate infections or be compounded by concurrent donors, poses unique engraftment problems. Transplants between
infections. In addition, because epithelial tissue repair may be delayed siblings completely matched at HLA-A, HLA-B, and HLA-DR loci are
by ongoing neutropenia and local microinvasive infection, delay rarely (1%–3%) associated with graft failure; however, the probability
in hematopoietic engraftment can exaggerate and prolong these of graft failure in the related-donor transplantation setting increases
toxicities. to near 10% with greater degrees of donor-recipient HLA incompat-
ibility. This may be overcome by the promising use of post-HCT
cyclophosphamide to deplete alloreactive host and particularly donor
Graft Failure cells. The problem is more frequently observed, although still <5%
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in the volunteer adult URD setting, where primary or secondary graft
Failure to establish hematologic engraftment (primary graft failure) failure may occur even after transplantation from donors well matched
and loss of an established graft (late graft failure) are serious, though at the HLA-A, HLA-B, HLA-C, and HLA-DR loci. In some cases, failure
uncommon complications of both autologous and allogeneic HCT. of URD stem cells to engraft may result from reactivity against other
Delayed or poor graft function can exaggerate and prolong the risks important histocompatibility determinants, including HLA-C or
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of infection and can increase the risk of peritransplant mortality. donor-specific antibodies against HLA class I or class II molecules.
Graft failure can occur if insufficient hematopoietic progenitors are Early failure of an allogeneic graft can be accompanied by emergence
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infused. A minimum of approximately 2 × 10 colony-forming cells of cytotoxic T-lymphocytes of host origin, presumably representing
from marrow per kilogram (kg) recipient weight are needed to immune-mediated graft rejection. This may be blunted by effective