Page 1796 - Hematology_ Basic Principles and Practice ( PDFDrive )

1600 Part X Transplantation

The likelihood of finding an optimal adult unrelated donor (i.e., a after cord blood grafts were 24% and 31%, respectively; correspond-
donor matched at high resolution at HLA-A, HLA-B, HLA-C, and ing incidences after haploidentical marrow grafts were 7% and 45%.
-DRB1) varies among racial and ethnic groups depending on the size The ongoing BMT-CTN 1101 study comparing umbilical cord
and composition of unrelated donor registries. Within the US popu- blood versus haploidentical marrow grafts will hopefully inform
lation, the highest likelihood for finding an optimal donor is for clinical decision making about the relative risks/benefits of these two
whites of European descent, at 75%, and the lowest among blacks of alternative donor sources.
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South or Central American descent, at 16%. The unrelated donor
search process can be time-consuming, raising the risk of disease
progression before transplantation can be performed. As a source of GRAFT VERSUS MALIGNANCY EFFECTS
hematopoietic stem cells for unrelated donor transplantation, umbili-
cal cord blood offers several advantages. It is readily available and Donor derived alloreactive cells are capable of mounting a potent
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entails no risk to the donor. Current data also indicate that HLA- anticancer immune response. Barnes and Loutit studied leukemic
matching criteria for cord blood transplantation need not be as mice treated with high-dose TBI and compared those receiving
stringent as for adult donor transplantation. Hence cord-blood units syngeneic and allogeneic bone marrow infusions. Mice receiving
mismatched at one or two HLA loci are available for almost all syngeneic marrow died quickly of leukemia whereas those receiving
patients <20 years of age and for more than 80% of patients ≥20 allogeneic cells survived longer but eventually developed fatal GVHD.
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years of age, regardless of racial and ethnic background. Drawbacks Importantly, the allografted mice had no evidence of leukemia at
of cord blood transplants include procurement costs, often limited death. Several canine and murine experiments reproduced these
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number of hematopoietic cells in each cord blood unit and relatively results. Antitumor effects of allogeneic cells could be specific, i.e.,
high rates of TRM. after sensitization of the donor or the donor’s cells to antigens present
The numbers of cord blood transplants have increased steadily, on malignant cells, or nonspecific, i.e., associated with GVHD, an
especially in children but also in adults. Comparative data on cord immune reaction of donor lymphocytes against normal and malig-
blood versus adult donor transplantation in adults come from registry nant host cells presumably triggered by differences in histocompatibil-
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studies and consistently suggests slower hematopoietic recovery but ity antigens. The term graft-versus-leukemia was coined by Bortin
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lower rates of GVHD with cord blood grafts. A CIBMTR compari- and coworkers to indicate the adoptive immunotherapeutic effect
son of adult leukemia patients receiving cord blood versus matched of transplanted donor cells against the recipient’s leukemia cells.
or mismatched unrelated marrow grafts indicated that rates of relapse, Clinical evidence for the importance of GVM effects in eradicating
TRM, treatment failure and overall mortality were not significantly tumor includes: 1) lower incidence of disease relapse in allograft
different between recipients of cord blood or mismatched marrow recipients with acute and/or chronic GVHD than in those without
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transplants. Based on current data, a one or two HLA-antigen GVHD ; 2) higher relapse rates after syngeneic versus allogeneic
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mismatched cord blood graft of appropriate cell dose is an accept- HCT ; 3) higher relapse rates after T-cell depleted transplants ; 4)
able alternative for patients with hematologic malignancies who durable remissions induced after posttransplant relapse by infusion
need HCT but do not have a readily available HLA-identical adult of donor lymphocytes without other antileukemia therapy; and 5)
(sibling or unrelated) donor. Patients without a single cord unit durable remissions achieved after very low doses of conditioning
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of adequate cell dose may receive two units to facilitate engraft- agents (e.g., 2 Gy TBI) and allogeneic HCT. GVM effects are associ-
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ment. Other approaches to facilitate engraftment with limited cord ated with GVHD and measures that prevent or suppress GVHD may
blood cell doses, including ex vivo cell expansion techniques are in allow more relapse but significant anticancer effects are demonstrable
clinical trials. even in the absence of clinically significant GVHD, especially in
HLA haploidentical related-donor HCT (mismatched at ≥2 loci AML and CML. The efficacy of immune-mediated antitumor effects
HLA-A, HLA-B, HLA-C and HLA-DR; usually parents, siblings, varies by disease; they are most evident in myeloid leukemias and
or children of patients) is another option for patients without indolent lymphomas.
matched sibling or unrelated donors. Despite the potential benefit The role of natural killer (NK) cells in the posttransplant setting
of a strong GVM effect, the risk of severe GVHD, graft rejection and is of increasing interest. After HCT, donor-derived NK cells promote
infectious complications have historically limited the applicability engraftment, reduce the risk of GVHD, enhance immune reconstitu-
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of haploidentical HCT. Newer strategies using intense ex vivo or tion and also decrease the risk of relapse especially in AML. In the
in vivo T-cell depletion or the use of cyclophosphamide posttrans- physiologic state, NK cells can engage and kill target cells lacking
plantation have improved the safety of haploidentical transplants. major histocompatibility (HLA) class I molecules. This function is
Immediate and near-universal donor availability, theoretically lower regulated by signaling through the KIR family. In the allogeneic HCT
costs and the potential to select donors with a favorable killer-cell setting; lack of expression of the inhibitory KIR ligand on the recipi-
immunoglobulin-like receptor (KIR) phenotype that enhances ent’s leukemic cells can trigger donor NK cell alloreactivity against
antileukemia activity are advantages. Limited retrospective data leukemia. The KIR family represents a second immunogenetic system
suggest haploidentical HCT performed using T-cell–replete grafts inherited independently of HLA that can affect transplant outcomes
and posttransplant cyclophosphamide achieves outcomes comparable especially relapse-free survival in AML. It has been proposed that in
with those of transplantation performed using matched related or the setting of HCT for AML, KIR genotyping be used in addition
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unrelated donors. Administration of high dose cyclophospha- to HLA typing by selecting donors with favorable KIR haplotypes.
mide posttransplantation promotes tolerance in alloreactive host In the setting of haploidentical and T-cell depleted HCT for myeloid
and donor T cells, leading to suppression of graft rejection and malignancies, donor-recipient KIR ligand mismatching is associated
GVHD without toxicity to donor hematopoietic cells. A variety of with favorable outcomes in some studies.
myeloablative and RIC haploidentical regimens with posttransplant
cyclophosphamide administration have been described and represent
another option for patients who lack timely access to a conventional PROGNOSTIC FACTORS
unrelated donor.
In patients lacking matched adult (sibling or unrelated) donors, Although allogeneic HCT has efficacy in hematologic malignancies,
the choice between cord blood versus haploidentical HCT is a matter the procedure carries a substantial risk of morbidity and mortality.
of much ongoing debate. The BMT-CTN conducted two parallel TRM may result from toxicity of the pretransplant conditioning
multicenter phase 2 trials in patients with leukemia or lymphoma regimen to lung, liver, and other organs, complications of cytopenia,
and no suitable adult donors using either double cord blood units or GVHD, and infection related to delayed immune reconstitution
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haploidentical marrow grafts (BMT-CTN 0603) after RIC. Survival especially in the setting of GVHD or its treatment. The risk of TRM
at 1 year was similar: 54% after cord blood HCT and 62% after may be 30% or higher in adults receiving unrelated or alternative
haploidentical marrow grafts. The incidence of TRM and relapse donor transplantation. In addition, many patients have recurrence of