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358 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 359

overall survival than paternal donors. 110,111 In contrast, a 2014 paper faster engraftment times seen with PBPC have enabled many centers to
reporting outcomes of HLA-haploidentical HCT in China found less pursue outpatient autologous HCT, further easing the logistical burden
GVHD and better overall survival with paternal compared to maternal on patients as well as treatment costs.
donors. As with previous studies, haploidentical siblings (particularly
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those disparate for noninherited maternal antigens) were associated Tumor Contamination in the Autograft
with the best outcomes. There is some preclinical evidence that exposure A consistent concern in autologous HCT is the possibility that resid-
to noninherited maternal antigens through breastfeeding may reduce ual tumor cells may contaminate the HSC product and contribute to
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the risk of GVHD in maternal-donor haploidentical HCT, and thus relapse. The relative contributions of autograft contamination and resid-
the disparate clinical results with maternal donors may be explained in ual disease in the patient are difficult, if not impossible, to distinguish.
part by variations in demographic patterns of breastfeeding. In view of Several investigators have approached this question by marking the
the conflicting state of the existing literature, there is no universal stan- HSC product at the time of harvest and then assaying for the marker
dard approach to selecting an HLA-haploidentical donor; the decision gene in malignant cells at the time of subsequent relapse. Studies using
is often guided by donor availability and health status, although the lit- this approach have been performed in patients with leukemia, lym-
erature arguably contains weak support to prefer HLA-haploidentical phoma, and myeloma, and have reached conflicting conclusions about
siblings over parents, and mothers over fathers, as donors. the contribution of autograft contamination to relapse. 114,115
A number of ex vivo and in vivo purging strategies have been inves-
tigated in autologous HCT. These include administration of rituximab
Comparison of Alternative Donor Options before autologous HSC collection in patients with CD20+ malignancies;
Although both UCB and HLA-haploidentical HCT have been estab- ex vivo positive selection for CD34+ cells; chemotherapy-based purging
lished as feasible and effective options for patients lacking conven- using CY derivatives; and purging via oncolytic viruses. 116–120 Single-arm
tional donors, the optimal alternative-donor source remains unclear. or uncontrolled studies have suggested a possible benefit in some of
Given the lack of robust comparative data, the choice between UCB these instances, but there is little or no evidence from randomized clin-
and haploidentical HCT is often guided by institutional experience, ical trials at present to support the efficacy of autograft purging, and its
comfort level, and research priorities. To address the relative merits of use remains investigational. One of the few randomized clinical trials
these approaches, the United States Blood & Marrow Transplant Clin- in the field concluded that in vivo purging with rituximab administered
ical Trials Network (BMT-CTN) conducted parallel multicenter phase before autologous HSC collection was as effective, and likely safer, than
II clinical trials of RIC followed by either UCB or haploidentical HCT ex vivo CD34+ selection. Another randomized clinical trial found
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(the latter using T-cell-replete marrow as a graft source and posttrans- that CD34+ selection significantly reduced autograft contamination
plantation CY as GVHD prophylaxis). These trials reported similar with myeloma cells, but did not improve clinical outcomes. Purging
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overall and disease-free survival at 1 year with the two approaches. strategies carry some potential for harm, as they deplete the autograft
UCB transplantation was associated with a higher risk of GVHD and of mature T cells and increase the risk of infectious complications, par-
nonrelapse mortality, while haploidentical HCT was associated with a ticularly CMV or other viral reactivation, after autologous HCT. 123,124 At
higher risk of relapse. Based on these results, the BMT-CTN is currently present, given the lack of convincing evidence of clinical benefit, purg-
conducting a national, multicenter phase III clinical trial randomizing ing strategies are not widely used and most centers collect and infuse
participants between UCB and haploidentical HCT. In addition to clin- unmanipulated autologous HSC (although these cells are often mobi-
ical outcomes, this trial is designed to measure quality-of-life and cost lized with a regimen containing chemoimmunotherapy, which arguably
differences between the two alternative-donor approaches in a compre- represents a form of in vivo purging). Because relapse remains a major
hensive effort to clarify their relative advantages and disadvantages.
concern after autologous HCT, ongoing research is focused on identi-
fying more efficient and clinically effective means of autograft purging.
CONCEPTS OF CURATIVE THERAPY
ALLOGENEIC HEMATOPOIETIC CELL
AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION
TRANSPLANTATION Allogeneic HCT is a considerably more complicated procedure than
The relationship between the dose of chemoradiotherapy administered autologous HCT. It involves more pretransplantation preparation, poses
and the number of tumor cells killed has been extensively studied in a greater risk of complications to the patient, is associated with a signifi-
vitro and in preclinical animal models, and forms the rationale for cantly higher rate of TRM, and requires at least temporary postgrafting
myeloablative autologous HCT. For chemosensitive tumors (includ- immunosuppression to enable engraftment and prevent GVHD. The
ing most hematologic malignancies), a steeply rising dose–response decision to pursue allogeneic HCT is based on diagnosis, prognosis, and
curve is observed. The curative potential of autologous HCT is, there- remission status, as well as the availability of an appropriate donor and
fore, derived from high-dose chemotherapy or chemoradiotherapy the psychosocial resources of the patient to cope with the demands of
administered as transplant conditioning to enhance tumor cell kill and the process. Decisions about eligibility for allogeneic HCT are typically
overcome drug resistance. This level of dose escalation is possible in made on a center-by-center and case-by-case basis, with inherent ele-
autologous HCT because dose-limiting toxicities to the hematopoietic ments of subjectivity and patient and physician judgment.
system are circumvented by the infusion of autologous HSCs, which A major obstacle to successful allogeneic HCT is the immune
rebuild hematopoiesis after high-dose conditioning. competence of the recipient. The potential to reject infused donor cells
Autologous HCT is associated with relatively low TRM. The use of is mediated predominantly through regimen-resistant host T and NK
mobilized PBPCs rather than marrow as a graft source has decreased cells. Strategies to reduce host immunity and promote donor hemato-
the duration of neutropenia, and when combined with improved sup- poietic cell engraftment include pretransplantation conditioning (most
portive care and patient selection has reduced the TRM associated with often chemotherapy and/or radiation) and postgrafting immunosup-
autologous HCT from approximately 8 to 10 percent in historical stud- pressive medications. Donor T cells in the allograft play a key role in
ies to 1 to 3 percent at most centers. In addition, the reduced risks and hematopoietic engraftment, and depletion of T lymphocytes from the

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