Page 1851 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 107 Unrelated Donor Cord Blood Transplantation for Hematologic Malignancies 1647

129
a portion of a single CB unit were cultured with TEPA and cytokines Preclinical data with aryl hydrocarbon receptor antagonists and
for 21 days and coinfused with the unmanipulated portion in 10 novel cytokines 130,131 with enhanced HSC expansion capacity are
115
patients. Although this technique led to an average expansion of promising approaches that are currently under investigation. The
+
219-fold for TNC and sixfold for CD34 cells, yet the time to University of Minnesota group presented the results of a phase I/II
hematopoietic recovery was not improved. The median time to study using StemReginin1 (SR1), an aryl hydrocarbon receptor
119
neutrophil recovery was 30 days and median time to platelets engraft- antagonist. This technique led to 328-fold expansion of CD34+cells
ment was 48 days. Of note, this study used tacrolimus and metho- resulting in 100% neutrophil engraftment in 17 DCBT patients after
trexate as GVHD prophylaxis, which may have contributed to myeloablative conditioning. The median time to neutrophil
116
delayed engraftment. Subsequently, Stiff et al reported a prospec- engraftment was shorter in 11 patients in whom the SR1-expanded
tive multicenter trial using this technique in patients undergoing cord predominated (11 days) compared with patients in whom the
single CBT with myeloablative conditioning, but replacing metho- unmanipulated cord predominated (23 days). This group are now
trexate with MMF. A portion of CB unit was expanded ex vivo and evaluating the safety and feasibility of infusing a single cord expanded
infused with the unmanipulated fraction of the same CB unit in 101 with SR1.
patients (median age 37 years). In contrast to the MDACC study, A different approach to improving engraftment is to enhance stem
this group attained an average expansion of 400-fold for TNC and cell homing to the BM niche. The Broxmeyer group reported that
+
77-fold for CD34 cells. Compared with DCBT controls from the endogenous CD26 expression negatively regulates the homing and
120
CIBMTR and the Eurocord registries, the times to neutrophil engraftment of stem cells. 120,121 Campbell et al evaluated pretreated
+
engraftment (21 versus 28 days, p < .0001) and platelet engraftment purified CD34 human CB cells with a CD26 peptidase inhibitor
(54 versus 105 days, p = .008) were significantly faster in the study (Ditropin A) and found a significant enhanced engraftment in NOD/
122
group. There were no differences in the rates of acute (19.4%) or SCID mice. Christopherson et al demonstrated that transplanta-
+
chronic (18.4%) GVHD and 100-day survival was significantly tion of either CD34 or lineage depleted human CB cells in NOD/
null
improved compared with the controls. SCID/B2m- mice after treatment with a CD26 inhibitor was
+
56
Delaney et al studied a double-unit CB strategy in which CD34 associated with a significant improvement in the engraftment of
selected CB progenitors were transduced with an engineered Notch long-term repopulating.
123
ligand (Delta1 ext-IgG ) and cultured for 16 days with cytokines. This led Cutler et al investigated the safety and efficacy of ex vivo treat-
+
to an average expansion of 562-fold for TNC and 164-fold for CD34 ment of one of the CB units with a prostaglandin E 2 (PGE 2 ) derivative
cells. A phase I study is ongoing in leukemia patients receiving mye- (dmPGE2) as a method to enhance engraftment by improved
loablative DCBT, in which an entire expanded unit is infused after the homing. The trial included 21 patients undergoing DCBT with
infusion of an unmanipulated unit. In the preliminary analysis (n = fludarabine, melphalan, and ATG (4 mg/kg) conditioning. During
10), the median time to neutrophil engraftment was 16 days. No their initial study period, the smaller CB unit was thawed on the day
infusional toxicities were noted but primary graft rejection occurred of transplantation and treated with dmPGE 2 for 60 minutes at 4°C,
in one patient. All evaluable patients developed grade II acute GVHD, but as the authors found two graft failures without any engraftment
except one who had grade III acute GVHD. There was no extensive improvement in this set of patients, they decided to treat the larger
chronic GVHD, while limited chronic GVHD was noted in three of the units at 37°C for 120 minutes. The treated CB unit was then
patients. Two patients had long-term persistence of the expanded cells, infused within 4 hours of the untreated unit. The median time to
until day 180 and day 240, but not beyond one year, after which the neutrophil engraftment was 24 days and 17.5 days in the two cohorts
unexpanded CB unit completely contributed to engraftment. respectively. The corresponding times for platelet engraftments were
The MDACC group explored another approach to expand CB 72.5 and 43 days. In the second cohort, 10 of 12 patients had 100%
CD34+ cells by coculturing with mesenchymal stromal cells derived hematopoiesis from the dmPGE 2 treated CB unit which was sustained
from either haploidentical family member BM or “off-the-shelf” for up to 27 months post-CBT.
117
132
universal donors. This approach was tested in a clinical trial in 31 Hidalgo et al found that the defect in CB homing was associated
patients (median age 31 years) after myeloablative DCBT and low with a reduced α-1,3-fucosyltransferase expression and activity in CB
+
dose rabbit ATG (1.25 mg/kg on day –4 and 1.75 mg/kg on day –3). CD34 cells, decreasing their ability to bind to P- and E-selectins
After 14 days of coculture, they achieved median 40-fold expansion expressed by the BM vasculature. Subsequently, investigators at the
+
133
of CD34+ cells and 14-fold for TNC. The expanded unit was infused MDACC demonstrated that human CD34 CB cells fucosylated
following the infusion of the unmanipulated unit. This resulted in using a recombinant fucosyl transferase in a murine model exhibited
significantly improved engraftment compared with the CIBMTR improved engraftment. The group reported results of their phase I
controls. The cumulative incidence of engraftment at day 42 was clinical trial using this approach in 22 adults undergoing myeloablative
96% (compared with 78% in the controls, p < .001), with faster or RIC DCBT and rabbit ATG (total dose 3 mg/kg infused over 2
neutrophil recovery (median 15 days versus 24 days, p < .001) and days), where one CB unit was infused unmanipulated while the other
platelet recovery (42 days versus 49 days, p = .03). The cumulative unit was ex vivo fucosylated for 30 minutes at room temperature
124
incidences of grade II–IV (42%) and III–IV acute GVHD (13%) before infusion. The cumulative incidence of neutrophil engraftment
and chronic GVHD (45%) were similar to the controls. In the 28 was 95.5% and all evaluable patients had 100% donor chimerism
evaluable patients, 54% had hematopoiesis derived solely from by day +30 posttransplantation. The median times to neutrophil
unmanipulated cord, while the rest had hematopoiesis derived from engraftment (17 days versus 26 days, p = .0023) and platelet engraft-
both units by day 30. At 6 months post-CBT, the expanded CB was ment (35 days versus 45 days, p = .0520) were significantly improved
detected in 13% of the patients. compared with the institutional historical controls. There were no
118
Horwitz et al reported results of a phase I clinical trial using differences in the cumulative incidences of acute grade II–IV GVHD
CB expansion with nicotinamide, which inhibits differentiation and (41%), acute grade III–IV GVHD (9%), or chronic GVHD (5%)
enhances functionality of hematopoietic stem and progenitor cells. compared with the controls. This approach is especially attractive
In this study, 11 patients (median age 45 years) received TBI-based as it is quick and does not require prolonged ex vivo culture or a
myeloablative conditioning DCBT, where the CD133+ selected Good Manufacturing Practice (GMP) laboratory, thus making it
fraction of one CB unit was expanded ex vivo for 3 weeks with nico- universally adoptable across centers. The multicenter phase III study
tinamide and then infused along with its CD133-fraction and a has been approved by the FDA and is expected to open to accrual soon.
second unmanipulated cord. This led to significantly improved Although these novel techniques have led to significant improve-
median times to neutrophil (13 days) and platelet (33 days) engraft- ment in the rapidity of hematopoietic recovery, the impact of these
ment compared with their institutional controls. One patient had strategies on immune reconstitution is still unclear. This is of interest
primary graft failure. Five patients developed grade II–IV acute because disease relapse is the leading cause of mortality and viral
GVHD and there was no cases of grade III–IV acute GVHD. One- infections (especially CMV, EBV, adenovirus, and BK virus) contrib-
year OS was 82% and PFS was 73%. ute to significant morbidity and mortality in the post-CBT period.