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Chapter 107 Unrelated Donor Cord Blood Transplantation for Hematologic Malignancies 1635

Transplant-Related Mortality and Survival units (HR ranging from 2.8 to 4.6 for 1 to 5 allele mismatches).
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The author recommended avoiding CB units with greater than three
Early series of single-unit CBT demonstrated high transplant-related allele mismatches. Of note, only 7% of the units in their study were
mortality (TRM) and consequently poor survival after single-unit complete allele matched and 90% of the 4/6 matched patients by
CBT. This likely related to the high-risk nature of the patient popula- current standard were reported to have greater than or equal to three
tion and standards of supportive care as well as the characteristics of allele-level mismatches. Therefore, if greater than three allele mis-
the transplanted units. Factors such as disease status and recipient matches are to be avoided, that would require massive addition of
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cytomegalovirus (CMV) positivity are strong determinants of survival high-quality CB units to the global inventory. Therefore, the
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after single-unit CBT. From the standpoint of the graft, both TNC application of the study results, which are highly informative, is
dose and HLA-match influence TRM and survival. In addition to impractical for current clinical practice.
low TNC dose being associated with increased TRM and decreased
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survival, 12,15,18,19 the 68 adult patient analysis of Laughlin et al and
+
19
the Wagner et al 102 patient analysis demonstrated a higher CD34 Comparison of Single-Unit Cord Blood Transplantation
cell dose (>1.2 and 1.7, respectively) were associated with significantly and Adult Donor Allografts
improved disease-free survival (DFS). Also, increasing HLA-mismatch
is significantly associated with increased TRM and lower survival. 12,19,27 Although the use of CBT as an alternative HSC source has increased
The 2010 NYBC analysis of combined TNC dose and HLA match substantially, no randomized studies evaluating survival after CBT
showed that recipients of 6/6 HLA-matched units had the lowest versus adult donor allografts have yet been reported. Retrospective
TRM and best survival regardless of the dose at least within the dose comparisons have demonstrated varying results depending on whether
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range tested (Fig. 107.3). Recipients of units with one HLA- the series evaluated children or adults and if matched versus mis-
7
mismatch and a TNC dose 2.5 to 4.9 × 10 /kg had a similar TRM matched unrelated volunteer donors were included. Selected series are
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as those receiving units with two mismatches and a TNC greater than summarized in Table 107.1. In 2007, Eapen and colleagues com-
7
5.0 × 10 /kg despite the higher cell dose in the latter group (see Fig. pared the outcomes of pediatric single-unit CBT with those of unre-
107.3). Recipients of single units with one or two mismatches and a lated volunteer BM recipients who were transplanted for the treatment
7
TNC below 2.5 × 10 /kg had very high TRM and poor survival. of acute leukemia. Compared with the recipients of 8/8 allele-matched
In the 2011 Eapen series evaluating the contribution of HLA-C unrelated donor BM transplantation (BMT), the 5-year LFS in recipi-
matching after single unit CBT, patients matched at HLA-A, HLA-B, ents of one or two HLA-mismatched CBT was similar. Notably,
and HLA-DRB1 had a higher TRM if mismatched at HLA-C (n = however, a significantly higher LFS was observed in recipients of 6/6
23; HR 3.97; p = .018) as compared with those matched at all four HLA-matched units. Interestingly, TRM was similar in 6/6 HLA-
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loci (n = 69). TRM was also higher in 5/6 but 6/8 matched CBT matched and 5/6 HLA-matched high cell dose compared with that of
recipients mismatched at one of HLA-A, HLA-B, or HLA-DRB1 allele-matched unrelated donor recipients’ transplant (p = .0659 and
plus HLA-C (n = 234; HR 1.70; p = .029) compared with those who .1332, respectively). By contrast, TRM was higher in recipients of one
were 5/6 and 7/8 matched (i.e., when there was a single HLA mis- antigen HLA-mismatched low cell dose and two antigen HLA-
match at HLA-A, HLA-B, or HLA-DRB1 but a match at HLA-C; mismatched of any cell dose compared with allele-matched unrelated
n = 127). This study suggests that HLA-C matching is an important donor recipients (p = .0455 and .0003, respectively).
determinant of survival and should be considered in unit selection A similar analysis done in adult patients with acute leukemia
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algorithms. In a recent study by Eapen et al using allele level demonstrated that single-unit CBT recipients had a higher TRM
matching, significantly higher nonrelapse mortality (NRM) was compared with recipients of 8/8 HLA-matched unrelated donor
noted with units mismatched at any number of alleles (HLA-A, transplants but a similar TRM to that of 7/8 HLA-mismatched
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HLA-B, HLA-C, or HLA-DRB1) compared with HLA-matched unrelated donor transplant recipients. The Japanese group of
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Takahashi et al compared CBT recipients with unrelated donor BM
or PB HSC transplantation for the treatment of hematologic malig-
nancies. They demonstrated a slower neutrophil recovery in CBT
100 recipients but a similar rate of neutrophil engraftment. The incidences
of grade III–IV acute GVHD and extensive chronic GVHD were
higher after unrelated donor transplantation. No differences were
CI of transplant-related mortality 60 + + + ++ + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ++ + + + + + + + + + + + + + + + + + + 1 MM/TNC <2.5 +++ + + + ++ + + unrelated donor BMT in patients with acute leukemia. The patients
80
demonstrated in TRM, relapse, or DFS between the groups. Atsuta
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et al conducted a disease-specific analysis comparing CBT to
2 MM/TNC <2.5
+ +
+
+
+
+
had similar age distribution, and all received myeloablative condition-
2 MM/TNC 2.5-4.9
+
+
+
ing. In the acute myeloid leukemia group, there was a similar relapse
+
+ + + +
rate but higher TRM in CBT recipients, resulting in lower survival,
+
1 MM/TNC 2.5-4.9
but similar relapse and survival rates were seen in the acute lympho-
+ +
40
+ +
+ + + + +
+ +
+
+
+
+
+
blastic leukemia (ALL) group. The risk of developing extensive
2 MM/TNC ≥5.0
+
+
+ +
+
1 MM/TNC ≥5.0
+ + ++ ++
20
DOUBLE-UNIT CORD BLOOD TRANSPLANTATION
+ + + + + + + + + + ++ + + ++ ++ ++ ++ + 0 MM (all doses; mean TNC, 4.4) ++ chronic GVHD was lower in CBT recipients.
0
0 1 2 3 The transplantation of HSC from more than one donor is an
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approach that was originally reported by Mathé et al, who infused
Time posttransplant (years) multiple aliquots of BM from different donors. In 1972, Ende and
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Fig. 107.3 CUMULATIVE INCIDENCE (CI) OF TRANSPLANT- Ende published the first case of allogeneic CBT using multiple small
RELATED MORTALITY (TRM) ACCORDING TO THE COMBINED CB units. Subsequently, double-unit CBT (DCBT) was formally
TOTAL NUCLEATED CELL (TNC) DOSE AND HUMAN LEUKO- investigated by the University of Minnesota as a method to augment
CYTE ANTIGEN MISMATCH AFTER SINGLE-UNIT MYELOABLA- graft cell dose. These investigators demonstrated the safety and fea-
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TIVE CORD BLOOD TRANSPLANTATION. MM, Mismatched. (From sibility of this approach. Barker et al reported two series of DCBT
Barker JN, Scaradavou A, Stevens CE: Combined effect of total nucleated cell dose after myeloablative and reduced-intensity conditioning (RIC) condi-
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and HLA match on transplantation outcome in 1061 cord blood recipients with tioning in patients with high-risk hematologic malignancies. The
hematologic malignancies. Blood 115:1843, 2010.) myeloablative series evaluated 23 patients (median age 24 years) and