Page 1844 - Hematology_ Basic Principles and Practice ( PDFDrive )

1640 Part X Transplantation

of conditioning specifically used in patients with DSAs was not transplant procedures and study designs. The following section
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reported. Similar to these findings, more recently Dahi et al also highlights some of these differences.
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showed no impact of DSAs on engraftment in 82 DCBT recipients In the BMTCTN-0501 randomized trial, a higher incidence of
who were transplanted with either myeloablative (82%) or nonmy- grade III–IV acute GVHD was noted in children receiving double-
eloablative (18%) conditioning. DSAs were present in about 15% of unit than those receiving single-unit CBT (23% versus 13%, p = .02).
patients, half of which targeted both CB units. There was no differ- Similarly, the incidence of chronic extensive GVHD was higher in
ence in cumulative incidence of engraftment at day 42 in patients the DCBT group at 1 year after transplantation (15% versus 9%,
with DSAs (92%), without DSAs (95%), or those with nonspecific p = .05). A retrospective study conducted by the Eurocord and Acute
HLA-antibodies (100%). Intriguingly, half of the patients with DSAs Leukemia Working Party of European Blood and Marrow Transplant
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against one CB unit actually engrafted with that unit. Of note, all (EBMT) group in adults with acute leukemia (n = 239) receiving
patients with DSAs in this study received myeloablative conditioning. myeloablative conditioning found higher risk of grade II–IV acute
Therefore, it is possible that the use of DCBT and myeloablative GVHD after DCBT compared with single CBT (43% versus 26%,
conditioning may overcome any potential adverse effect of DSAs. p = .005); however, two-thirds of these events were grade II acute
Some of the differences in these studies could be explained by differ- GVHD. Age less than 35 years (HR 0.55, 95% CI, 0.34–0.88, p =
ences in underlying patient population, type of conditioning regimen, .01) and the use of single CBT (HR 0.84, 95% CI, 0.41–0.96, p =
GVHD prophylaxis, use of ATG or not, assay used to detect DSAs, .02) were independently associated with lower risk of acute GVHD.
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threshold for labeling DSAs as positive and the median fluorescence In a retrospective analysis by MacMillan et al comparing single-
intensity of DSAs. Although virtual cross-match techniques may be unit (n = 80) and double-unit (n = 185) CBT, the incidence of grade
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used to screen for DSAs, it is debatable if their presence should be II–IV acute GVHD was noted to be significantly higher in recipients
assessed in all patients being considered for CBT. It certainly adds to of DCBT (58% versus 39%, p < .01). However, the increased risk
health care costs and may delay search for an “appropriate” unit. was predominantly accounted by grade II skin acute GVHD, and the
overall incidence of grade III–IV acute GVHD was similar among
DOUBLE-UNIT VERSUS SINGLE-UNIT CORD the groups (19% versus 18%). Of note, differential use of ATG,
differences in age, year of transplant, conditioning regimens and
BLOOD TRANSPLANTATION GVHD prophylaxis between the groups are some of the important
biases in the study. For instance, the single CBT group was younger
Engraftment (median age 23 years) and ATG was used in more than half of them.
In contrast, the median age of patients in the double-CBT group was
The use of double-unit CB grafts is now a standard approach to 45 years and only about a quarter received ATG. Younger age and
augment cell dose, although DCBT does not improve or hasten higher use of ATG may explain lower incidence of acute GVHD seen
engraftment compared with adequately dosed single-unit CBT. 75–77 after single CBT.
A recent phase III, multicenter, randomized trial conducted by the On the other hand, the CIBMTR-NYBC registry analysis of
Blood and Marrow Transplant Clinical Trials Network (BMTCTN) adequately dosed single (n = 106, median age 33 years) or double
in collaboration with Children’s Oncology Group (BMTCTN-0501 (n = 303, median age 43 years) CBT in adults also showed signifi-
trial), involving children (median age 9.9 years) with hematologic cantly higher risk of grade II–IV acute GVHD in recipients of DCBT
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malignancies compared the use of single (n = 112) with double (n = compared with single CBT. However, this increased risk was noted
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108) CBT after myeloablative conditioning. The study found no only during the early study period (2002–2004), but not in the later
difference in the incidence of neutrophil recovery (88% versus 89%), period (2005–2009). In the early period, the day 100 probabilities
or the time to neutrophil engraftment between the groups (23 versus of grade II–IV acute GVHD after single and DCBT were 18% and
21 days respectively). On the contrary, the recipients of single CBT 58% respectively (p < .001). In the later period, the corresponding
had significantly faster platelet engraftment compared with DCBT probabilities were 27% and 31% respectively. Likewise, there were
recipients (median 58 versus 84 days, respectively). no differences in the rates of grade III–IV acute GVHD (14% versus
In the absence of a randomized controlled trial in adults, data 18%) or chronic GVHD at 2-years (24% versus 31%) among the
from retrospective series and a small prospective study suggest similar groups. Notably, significantly more patients in the single CBT group
rapidity and cumulative incidence of engraftment between single or received myeloablative conditioning compared with DCBT group
double CBT recipients. A retrospective analysis of the CIBMTR and (72% versus 45% respectively, p < .0001). As the use of myeloablative
the NYBC registries compared single (n = 106) with double (n = regimens is generally associated with a higher risk of GVHD com-
303) CBT after myeloablative (n = 216) or RIC regimens (n = 193) pared with RIC regimens, this may have biased the study results.
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in adults with acute leukemia. The median time to neutrophil Another study in patients with lymphoid malignancies (n = 104,
engraftment (20 days in both groups) and the probability of neutro- median age 41 years), found no impact of using single or double CBT
phil engraftment by day 42 were identical in both groups (81% after after RIC regimens on the incidences of acute or chronic GVHD. 83
single CBT versus 78% after DCBT, p = .83). The effect of in vivo T-cell depletion on GVHD has also been
A prospective study in adults (median age 53.5 years) compared investigated. 84–87 However, the results across studies must be inter-
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single CBT (n = 27) with DCBT (n = 23) after RIC regimens. preted with caution, taking into consideration the type of in vivo
Patients underwent single CBT if cryopreserved TNC dose in one depletion used (ATG, ALG, or alemtuzumab), type of ATG used
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unit was >2.5 × 10 /kg recipient weight. Once again, there were no (rabbit versus horse), dose (high versus low) and the timing (early
differences in the median time to neutrophil engraftment among versus delayed) in addition to baseline patient characteristics and
single CBT (25 days) or DCBT (23 days), or the cumulative inci- transplant practices.
dence of neutrophil engraftment at day 100 posttransplantation A study evaluated the impact of rabbit ATG (total dose 10 mg/
(88.4% versus 91.3% respectively, p = .99). kg) on CBT outcomes in 127 children after either myeloablative or
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RIC regimens. GVHD prophylaxis consisted of cyclosporine with
either prednisolone or mycophenolate mofetil (MMF). Patients were
Graft-Versus-Host Disease divided into three groups: early ATG group (between days −9 and
−5), late ATG group (between days −5 and 0), and no-ATG group.
GVHD is a major cause of morbidity and one of the leading causes The study found an increased risk of acute GVHD and lower rates
of mortality after DCBT. 22,26,38,78–81 Also, DCBT may be associated of viral infections and infection related deaths in the group that did
with an increased incidence of acute GVHD compared with single not receive ATG compared with the groups that did. Further, the
CBT in a specific subset of patients, especially if transplantation is risk of acute GVHD was significantly higher in the no-ATG group
performed without the use of ATG or ALG. 78,82 The results across (HR 8.2, p < .001) and early-ATG group (odds ratio [OR] 3.9, p =
studies are variable because of heterogeneity in study population, .005) compared with the late-ATG group. However, there were no