Page 1845 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 107 Unrelated Donor Cord Blood Transplantation for Hematologic Malignancies 1641

differences in chronic GVHD or other outcomes including neutro- compared with single CBT in certain patients, 36,42,83 while other
phil engraftment, NRM, relapse and OS between the groups. studies did not find a similar association. 76,81
Although patients in the early-ATG group had significantly faster The Eurocord-Netcord investigators showed that the use of
CD3+, CD4+, and CD4+-naive T-cell immune reconstitution at 1 DCBT with either myeloablative conditioning or RIC was associated
and 2 months post-CBT compared with patients in the late-ATG with a significantly lower risk of relapse or progression at 2-years
group, yet, there were no differences in viral reactivation episodes in compared with single CBT (13% versus 38%; p = .009) in adults
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early and late-ATG groups. This is likely related to attainment of with lymphoid malignancies, but without any difference in DFS.
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similar immune reconstitution by 3 months post-CBT in both Verneris et al analyzed the risk of acute leukemia relapse in 177
groups. Therefore, the early use of ATG does not offer any clinical recipients of myeloablative CBT and found that for patients in first
advantage over not using ATG at all. or second complete remission, the risk of relapse was markedly
Series of DCBT in adults incorporating ATG have demonstrated reduced in DCBT recipients compared with single CBT recipients
lower rates of GVHD than what is typically seen after CBT without (19% versus 34%, p = .03). Again, no differences in leukemia-free
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the use of ATG. For example, Cutler et al reported an overall survival (LFS) were noted between the groups (55% in single and
incidence of grade II–IV acute GVHD of 9.4% and chronic GVHD 58% in DCBT group at 1-year, p = .35). However, the single CBT
of 12.5% in adults (n = 32, median age 53 years) after RIC using group included pediatric patients (n = 84, median age 8 years) while
rabbit ATG (days –7, –5, –3, –1; total dose 6.0 mg/kg) and GVHD the DCBT arm included mostly adults (n = 93, median age 24 years).
prophylaxis with sirolimus plus tacrolimus. Unsurprisingly, immune Another study in 110 adults with various hematologic malignancies
reconstitution was remarkably prolonged; the CD4+CD45RA+, noted a trend towards lower relapse after DCBT with nonmyeloabla-
CD4+CD45RO+, and CD4+CD25+ T-cell subsets did not reach the tive conditioning (30% versus 41%, p = .07) and significantly
pretransplantation levels even at 2-years posttransplantation. Conse- improved 3-year DFS after DCBT (39% versus 24%, p = .05)
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quently, five patients developed Epstein Barr virus (EBV) reactivation compared with single CBT. Another large registry study (n = 239)
leading to fatal posttransplant lymphoproliferative disorder and five by the Eurocord and the EBMT group in adults with acute leukemia
additional patients died of sepsis (4 caused by human herpesvirus-6 in first complete remission receiving myeloablative conditioning
and EBV-related meningoencephalitis). The NRM at 2-years was found significantly improved 2-year DFS in DCBT group (48%) and
34.4%, which is considerably higher than what is reported by other single CBT patients who received thiotepa/busulfan/fludarabine
RIC CBT series. 78,86,88–94 Another study included 42 adults RIC conditioning (48%), compared with single CBT performed with
DCBT patients (median age 49 years) who received rabbit ATG and either busulfan- or TBI-based conditioning (30%), p = .003. No
tacrolimus/sirolimus (69%) or cyclosporine based (31%) GVHD difference in the risk of relapse at 2-years (20% versus 19%, p = .72)
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prophylaxis. The dose and timing of ATG were not mentioned. was noted in single or double CBT recipients respectively. Of note,
Although there were low incidence of grade II–IV acute GVHD DCBT recipients were younger, received higher cell dose, and ATG
(21%) and chronic GVHD (24%), but as expected, T-cell immune was used less frequently than other groups.
reconstitution was substantially prolonged. The median number of Contrarily, the CIBMTR-NYBC registry study of adult leukemia
+
CD4 T cells did not reach >200 cells/mL even 9 months post- patients did not find any difference in 2-year probabilities of relapse
transplant leading to high rate of early infection (59%) within the (32% versus 36%) or DFS (30% versus 32%) after single or double
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first 100 days after transplantation. Similarly, Brunstein et al showed CBT, respectively. Correspondingly, the BMTCTN-0501 phase III
an increased risk of EBV–related complications with the use of high randomized study in pediatric patients found similar rates of 1-year
dose equine ATG (15 mg/kg given every 12 hours for 6 doses, days relapse (12% versus 14%, p = .12) and DFS (70% versus 64%,
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–5, –4, and –3) after Fludarabine/Cytaradine/total body irradiation p = .11) among single-unit or DCBT recipients respectively. There-
(TBI) RIC regimen but not after myeloablative regimens. The inci- fore, it is likely that the dissimilarities in relapse or DFS risk noted
dence of EBV–related complications was 3.3% in patients with across studies are reflections of differences in patients, disease type,
myeloablative CBT, but in patients with RIC CBT the incidence was risk and remission status, and transplant characteristics.
21% if ATG was used and 2% if was omitted, p < .01.
Although the use of ATG is associated with a higher risk of serious
infections, including fatal EBV–related complications, 85,87,95 delayed Nonrelapse Mortality and Overall Survival
immune reconstitution, 85,86,96 increased risk of TRM, 36,83 and possibly
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increased risk of relapse, the exclusion of ATG on the other hand In general, the use of myeloablative conditioning is associated with
is associated with an increased incidence of acute GVHD. Series of lower risk of relapse at the expense of higher toxicity and NRM. On
studies from MSKCC omitted the use of ATG in DCBT recipients the other hand, RIC regimens are well tolerated and result in lower
after either myeloablative (70%, median age 24 years) or RIC (30%, TRM but are associated with higher risk of relapse, thus resulting in
median age 10 years). 78,98,99 GVHD prophylaxis consisted of a calci- similar OS as seen after myeloablative conditioning. 104,105 The use of
neurin inhibitor and MMF. The omission of ATG led to rapid T-cell double-unit graft does not add to NRM compared with the use
+
immune reconstitution (median CD4 T-cell count >200 cells/µL by of single CBT. 42,76,77,81 The average 2–3 year cumulative incidence of
day 120 post-CBT) with resultant low incidence of serious infections NRM reported by various DCBT studies is about 20% to 45% and
or deaths caused by infections. Consequently, cumulative incidence OS is in the range of 35% to 65%, which are comparable with those
of 2-year TRM was low (21% at day +100 and 25% at 2-years), but observed after single CBT.
cumulative incidences of grade II–IV acute GVHD were high (43%). The BMTCTN-0501 randomized trial in pediatric patients
Thus, better understanding of the pathophysiology of GVHD reported similar 1-year OS (65% versus 73%; p = .17) and 1-year
after DCBT is needed to incorporate effective prevention and treat- TRM (19% versus 22%; p = .43) among single-unit or DCBT
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ment strategies balancing the risks of GVHD and infections. recipients respectively. In adults, the Eurocord and the EBMT
registry study found similar 2-year NRM after myeloablative single
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or double CBT (38% versus 34%, p = .95). Similarly, the CIBMTR-
Relapse and Disease-Free Survival NYBC registry analysis found a trend toward lower 6-month probabil-
ity of TRM after DCBT compared with single CBT (21% versus
Disease relapse is the most common cause of mortality after CBT, 31%, p = .06) in adult patients with acute leukemia, without any
contributing to 30% to 60% of deaths. In general, various DCBT difference in 2-year OS (35% versus 33%, p = .66). 76
studies reported an average relapse risk of approximately 10% to 35% Studies also imply that DCBT recipients who survive early post-
and DFS of about 30% to 55% at 2–5 years depending upon under- transplant period are very unlikely to die of delayed transplant-related
lying patient characteristics, disease risk and type, type of condition- causes. In the MSKCC series of DCBT recipients of either myeloab-
ing regimen and transplant practices. 38,76,79,81,100–103 A few retrospective lative (n = 53; 71%) or nonmyeloablative (n = 22; 29%) condition-
series suggest that DCBT is associated with a lower risk of relapse ing, 2-year TRM of 25% was almost entirely accounted for by