Page 1825 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 106 Haploidentical Hematopoietic Cell Transplantation 1627

improved by, the use of PBSCs. The substitution of PBSCs for bone Posttransplant cyclophosphamide has also been compared with
marrow would be expected to produce higher rates of chronic ATG as GVHD prophylaxis after HLA-haploidentical SCT for
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GVHD, although it is not obvious if this is indeed true for PTCy. patients with AML. 174a Patients in the PTCy group (n = 193) had
Three studies investigating the replacement of bone marrow with significantly less severe (grades III–IV) acute GVHD than the 115
PBSCs have shown higher but still favorable rates of chronic patients in the ATG group (5% vs. 12%, respectively; p = .01); the
GVHD, 154,155,157 whereas two others have demonstrated rates of incidence of chronic GVHD was not significantly different. Recipi-
chronic GVHD similar to those seen using haploBMT plus ents of PTCy had a significantly lower incidence of NRM (22% vs.
PTCy. 158,159 In these studies, the rates of grades III–IV acute GVHD 30%; p = .02), with no difference in relapse incidence. Compared
and NRM were not consistently higher than previously seen in with patients in the ATG group, patients receiving PTCy had
patients who received bone marrow. A matched pairs analysis found improved LFS (HR, 1.48; 95% CI, 1.03–2.12; p = .03) and a trend
no significant increase in the incidence of acute or chronic GVHD for higher OS (HR, 1.43; 95% CI, 0.98–2.09; p = .06). Taken
or NRM, but relapse incidence was significantly lower and event-free together, these results suggest that TCR haploBMT with PTCy may
survival was significantly improved with HLA-haploidentical PBSC be associated with a lower incidence of NRM, a similar incidence of
grafts as compared with bone marrow. 161 disease relapse, and improved LFS compared with haploSCT using
HaploBMT with PTCy has generally been well tolerated, although either megadose T cell–depleted grafts or TCR grafts with ATG-
a few potential complications are of particular note. Fever character- based prophylaxis.
istically occurs within the first few days posttransplant, particularly
when using PBSCs. 154,156,162 These fevers can become quite severe, are Integrating HLA-Haploidentical SCT Into Clinical
generally culture negative, and are thought to be cytokine mediated
and related to uncontrolled alloreactivity; therefore they tend to abate Practice: Comparison of Outcomes With Other
within hours to days of cyclophosphamide administration. Severe Graft Sources
cytokine release syndrome has been reported in patients receiving
HLA-haploidentical PBSCs and posttransplant cyclophosphamide, A long-standing dogma in the field of allogeneic SCT has been that
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and it is associated with increased NRM. In these cases, the syn- (1) HLA-matched sibling donors are associated with the best outcomes;
drome is associated with elevated serum levels of IL-6, and symptoms (2) if an HLA-matched sibling donor is not available, the next best
of cytokine release syndrome can be abated by the administration of donor is a well-matched (10/10 allele match at HLA-A, HLA-B,
tocilizumab, a humanized antibody against IL-6. Hemorrhagic cysti- HLA-Cw, HLA-DRB1, and HLA-DQB1) URD; and (3) in the
tis occurs not infrequently after haploBMT with PTCy, but it gener- absence of a well-matched sibling or URD, the choices boil down to
ally is of limited severity and is regularly attributable to polyomavirus partially HLA-mismatched adult URDs, URD umbilical cord blood,
(predominantly BK virus) infection. 154,164–166 Graft rejection remains and HLA-haploidentical first-degree relatives (Table 106.1). It is worth
a potential complication of haploBMT using either PTCy or TCD noting that no prospective, randomized trials comparing different graft
and can be related to DSA present pretransplant in the recipient. 19,52 sources have been published, so the dogma is based upon retrospective,
In patients with detectable DSA to all potential HLA-haploidentical registry-based studies. Several recent studies, albeit nonrandomized,
donors, desensitization procedures can reduce DSA titers such that call into question the positioning of HLA-haploidentical SCT at or
haploBMT can be performed successfully. 19,167,168 Notably, Epstein- near the bottom of the list of preferred donors.
Barr virus–related posttransplant lymphoproliferative disease within
the first year posttransplant was not seen among 785 patients treated
169
with PTCy, and no increase in donor-derived malignancies was HLA-Haploidentical BMT Versus UCBT
detected. 170
The Acute Leukemia Working Party of the European Blood and
Marrow Transplant Organization compared outcomes after UCBT
PTCy in Other Transplant Settings and haplo-SCT in adults with de novo AML (n = 918, comprising
360 haploSCT, 558 UCBT) and ALL (n = 528, comprising 158
175
PTCy has shown promise in facilitating solid-organ transplant. One haploSCT, 370 UCBT). Conditioning regimens were a mixture
group reported an approach to combined kidney transplant/BMT in of myeloablative conditioning and RIC, and GVHD prophylaxis
which fludarabine/cyclophosphamide conditioning was administered for recipients of haplo transplants included PTCy in 163, ATG
before renal transplant and column-selected PBSCs were given the in 244, and neither ATG nor PTCy in 111. UCBT was associ-
day after renal transplant. 171–173 MMF and tacrolimus were started 2 ated with delayed engraftment and a higher incidence of graft
days before kidney transplant and PTCy was given at 50 mg/kg 3 failure, but a lower incidence of chronic GVHD, for both AML
173
days posttransplant. According to the latest report, 12 of 19 patients and ALL patients. There were no significant differences between
achieved functional tolerance as demonstrated by successful cessation graft sources in the incidence of NRM or relapse or in LFS. The
of all immunosuppression without graft rejection; tolerance induc- authors concluded that both haplo and UCBT grafts are accept-
tion appeared to be dependent on achieving sustained donor able approaches for patients with acute leukemia lacking an HLA-
chimerism. 172 matched donor.
The Blood and Marrow Transplant Clinical Trials Network (BMT
Studies Comparing Modern Haploidentical CTN) in the United States conducted two parallel trials of RIC
followed by either double-UCBT (dUCBT) (BMT CTN 0604) or
Transplant Platforms HLA-haploidentical BMT with posttransplant cyclophosphamide for
patients with acute leukemia or lymphoma. 176,177 The 100-day cumu-
There are only two published studies comparing different HLA- lative incidence of grades II–IV acute GVHD was 40% after dUCBT
haploidentical transplant platforms. In both of them, data were and 32% after haploBMT. The 1-year cumulative incidence rates of
analyzed retrospectively. In a retrospective study of 65 adult patients NRM and relapse after dUCBT transplant were 24% and 31%,
receiving haploBMT using either PTCy or megadose T cell–depleted respectively, with corresponding results of 7% and 45% after hap-
stem cells for GVHD prophylaxis, survival was significantly better loBMT. OS and PFS were 39% (95% CI, 26%–53%) and 36%
174
after PTCy. Disease progression was similar between the patient (95% CI, 23%–49%), respectively, after dUCBT and 54% (95% CI,
groups; therefore this difference was largely a result of markedly lower 39%–67%) and 35% (95% CI, 21%–48%), respectively, after hap-
NRM after PTCy (16% vs. 42% at 1 year) with a lower risk of viral loBMT. The similar PFS seen in these two trials provided equipoise
(twofold lower) and fungal (fivefold lower) infections. Following for the current phase III, prospective randomized BMT CTN trial
PTCy, T-cell reconstitution was more rapid, and the incidence of (ClinicalTrials.gov identifier NCT01597778) comparing these two
chronic GVHD was lower (7% vs. 18%). different graft sources after RIC.