Page 1790 - Hematology_ Basic Principles and Practice ( PDFDrive )

1594 Part X Transplantation

become activated by exposure to host antigens and further activate and second transplants. Chemotherapy may induce some responses
other immune effectors, resulting in secretion of cytokines and clini- but rarely results in long-term disease control. Increasing knowledge
cal manifestations of GVHD. Chronic GVHD is defined as GVHD of the molecular basis of graft-versus-tumor responses has stimulated
occurring after day 100 after transplant, although this definition is interest in the use of immunotherapy to treat relapse. Infusion of
somewhat arbitrary. Chronic GVHD often occurs in a patient who unmanipulated donor lymphocytes can result in significant clini-
has had preceding acute GVHD, although it may arise de novo. It cal responses in patients with relapsed CML, but responses are less
23
targets the skin, liver, and gastrointestinal tract but may also target frequent in other hematologic malignancies. More recently, T cells
other organs and shares features with autoimmune diseases such as genetically modified with chimeric antigen receptors have shown
scleroderma. very encouraging response rates when treating relapse of CD19+ve
malignancies after autologous or allogeneic transplant, but longer
follow up is needed. 24–26 Other current research is focusing on
Graft Failure targeting lineage-specific antigens, such as Wilms Tumor 1, prefer-
entially expressed antigen of melanoma, or proteinase 3 or mutation
27
Graft failure results when recipient immune system cells that survive specific antigens. Additional immunotherapy approaches under
the conditioning regimen are able to eliminate the incoming donor investigation include the administration of antitumor vaccines or
BM. It is uncommon after fully ablative allogeneic HSCT for hema- NK cells. 28
tologic malignancies, but higher incidences are seen after reduced-
intensity conditioning and when cord blood is the source of HSCs.
Other risk factors include the degree of mismatch between donor and FUTURE DIRECTIONS
recipient, a low nucleated cell dose, and T-cell depletion of the donor
product. Patients who experience graft failure may be retransplanted An ongoing challenge is to delineate the indications for transplant as
after additional immunosuppressive conditioning, but mortality from new drugs are incorporated in primary therapies for many hemato-
infection caused by prolonged neutropenia is significant. logic malignancies and as risk factors continue to be redefined by new
information from genetic sequencing and proteomics studies. The
wider use of reduced-intensity transplant offers the prospect of using
Infections such transplants as a platform for immunotherapy, and transplant
will likely be integrated more closely with other cell therapies such
After engraftment of the donor HSCs, donor-derived cells reconsti- as infusions of NK cells, cytotoxic T cells, and regulatory T cells. The
tute the recipient’s immune system. This is usually a rapid process question of optimal stem cell source for patients who lack a matched
after autologous transplant but is more prolonged after allogeneic sibling or 10/10 matched unrelated donor is an open issue as novel
transplant and may be further delayed in a recipient who develops regimens to improve outcomes are being evaluated for cord and
GVHD and requires additional immunosuppression. During the haploidentical transplants. Finally, there is a need for comparative
early period after HSC infusion, neutropenic patients are at risk for effectiveness studies that include quality of life measures to compare
bacterial infection, fungal infection, and infection with respiratory transplant with other therapeutic options.
viruses (see Chapter 89). After engraftment, allogeneic recipients are
at risk for viral infection, particularly reactivation of herpes viruses
such as cytomegalovirus. Late infectious complications are mainly REFERENCES
seen in allogeneic recipients, in whom a major risk factor is chronic
GVHD. International consensus guidelines on the management of 1. Appelbaum FR: Hematopoietic-cell transplantation at 50. N Engl J Med
infections posttransplant have been published. 21 357(15):1472–1475, 2007.
2. Jenq RR, van den Brink MR: Allogeneic haematopoietic stem cell
transplantation: individualized stem cell and immune therapy of cancer.
Regimen-Related Toxicity Nat Rev Cancer 10(3):213–221, 2010.
3. Anasetti C: Use of alternative donors for allogeneic stem cell transplanta-
A number of early and late posttransplant complications are related tion. Hematology Am Soc Hematol Educ Program 2015:220–224, 2015.
to the conditioning regimen as well as previous therapies and pre- 4. Nunes E, Heslop H, Fernandez-Vina M, et al: Definitions of histocom-
transplant comorbidities. These include pneumonitis, sinusoidal patibility typing terms. Blood 118(23):e180–e183, 2011.
obstruction syndrome, hemorrhagic cystitis, growth impairment, and 5. Venstrom JM, Pittari G, Gooley TA, et al: HLA-C-dependent preven-
endocrine abnormalities and are described in Chapter 109. tion of leukemia relapse by donor activating KIR2DS1. N Engl J Med
367(9):805–816, 2012.
6. Warren EH, Zhang XC, Li S, et al: Effect of MHC and non-MHC
Secondary Malignancies donor/recipient genetic disparity on the outcome of allogeneic HCT.
Blood 120(14):2796–2806, 2012.
After HSCT, recipients have a twofold to sevenfold increased risk of 7. Gratwohl A, Pasquini MC, Aljurf M, et al: One million haemopoietic
developing a secondary neoplasm, with the most frequently seen stem-cell transplants: a retrospective observational study. Lancet Haema-
malignancies being Epstein-Barr virus-related posttransplant lympho- tol 2(3):e91–e100, 2015.
proliferative disease (EBV-PTLD), therapy-related AML and myelo- 8. Kollman C, Spellman SR, Zhang MJ, et al: The effect of donor charac-
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dysplasia, and a variety of solid tumors. As discussed earlier, teristics on survival after unrelated donor transplantation for hematologic
autologous transplant recipients are at risk of developing therapy- malignancy. Blood 127(2):260–267, 2016.
related MDS and AML because of previous therapy as well as 9. Kekre N, Antin JH: Hematopoietic stem cell transplantation donor
transplant conditioning. Recipients of allogeneic transplant have an sources in the 21st century: choosing the ideal donor when a perfect
increased incidence of both PTLD and solid cancers. match does not exist. Blood 124(3):334–343, 2014.
10. Brunstein CG, Fuchs EJ, Carter SL, et al: Alternative donor transplanta-
tion after reduced intensity conditioning: results of parallel phase 2
Treatment of Relapse trials using partially HLA-mismatched related bone marrow or unrelated
double umbilical cord blood grafts. Blood 118(2):282–288, 2011.
Relapse remains a major cause of treatment failure after HSCT 11. Li L, Li M, Sun C, et al: Altered hematopoietic cell gene expression
for hematologic malignancies, and present treatment options are precedes development of therapy-related myelodysplasia/acute myeloid
inadequate. Maneuvers that are commonly used are withdrawal of leukemia and identifies patients at risk. Cancer Cell 20(5):591–605,
immune suppression, donor lymphocyte infusions, chemotherapy, 2011.