Page 1104 - Hematology_ Basic Principles and Practice ( PDFDrive )

974 Part VII Hematologic Malignancies

Umbilical Cord Blood sibling donor predicted for 3-year survival ranging between 42%
(zero risk factors) and 6% (three or more risk factors). The major
Another important issue is the use of UCB transplantation for AML cause of death remains AML relapse, and innovative strategies to
in CR1. These data are harder to interpret because most studies have reduce leukemic burden before transplantation and enhance GVL
reported outcomes for “acute leukemia,” rather than restricted to effect after transplantation are required to improve survival of this
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AML-CR1. A European registry study documented similar outcomes extremely high-risk patient population. In this patient population,
of UCB versus unrelated donor bone marrow (BM) transplantation the ability of novel agents for targeting specific AML molecular
in adults with acute leukemia, whereas a CIBMTR study showed lesions or pathways (e.g., FLT3-ITD, IDH 1/2, mTOR) with limited
better outcomes with HLA-matched unrelated donor BM transplan- off-target toxicity, as a bridge to allogeneic HSCT, would be an
tation but similar outcomes of UCB and HLA-mismatched unrelated important albeit putative clinical benefit. The ability to rapidly
donor BM transplantation. 30,31 A large analysis of adult acute leuke- proceed to allogeneic transplantation may also be important given
mia (including 880 AML patients) compared the outcomes of single- the dismal outcome of chemotherapy alone, suggesting a role for
unit 4–6/6 HLA-matched (HLA-A, -B, -DRB1) UCB with 8/8 or expeditious UCB and haploidentical BM transplantation in this
7/8 HLA-matched (HLA-A, -B, -C, -DRB1) BM or peripheral blood setting, especially for patients achieving a remission.
stem cell (PBSC) transplantation and documented similar leukemia-
free survival regardless of stem cell source or degree of HLA match.
There was higher treatment-related mortality after UCB transplanta- Therapy-Related and Secondary
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tion. Transplantation in CR1 resulted in similar 2-year leukemia- Acute Myeloid Leukemia
free survivals of 44%, 50%, 52%, 39%, and 41% with UCB, 8/8
PBSC, 8/8 BM, 7/8 PBSC, and 7/8 BM transplantation, respectively. Therapy-related AML (t-AML) currently accounts for approximately
In contrast, a Japanese study evaluated outcomes of 484 AML patients 10% to 20% of newly diagnosed AML, and its incidence is likely to
receiving 4–6/6 UCB compared with 8/8 unrelated donor BM rise in the future given increasing cancer survivorship. Postremission
transplantation and documented a similar relapse risk with UCB therapy using conventional chemotherapy is usually not curative in
transplantation, but higher treatment-related mortality and worse secondary AML (s-AML: t-AML and AML arising from antecedent
overall and leukemia-free survival. 33 MDS or MPD) with the rare exception of CBF-AML, specifically
Double-unit UCB (DUCB) transplantation is commonly used for inv(16) and t(15;17). Allogeneic HSCT is less effective in s-AML.
larger patients. Indeed, since 2005 the number of adults receiving The poorer survival appears multifactorial, because of poor-risk
DUCB has exceeded those receiving single-unit UCB products. cytogenetics, lower likelihood of entering remission, older patient
Limited data suggest similar outcomes of myeloablative DUCB, age, and impaired organ function from prior cancer therapy; although
HLA-matched unrelated, and sibling donor HSCT in hematologic some reports documented similar posttransplantation survival com-
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malignancies. However, only a subset of patients had AML. The pared with de-novo AML when adjusted for risk factors like disease
role of DUCB in AML remains to be better delineated. Reducing status and cytogenetics. 2,45 An observational analysis of 545 patients
treatment toxicity will be important to advance UCB transplantation. with t-AML identified four risk factors influencing HSCT outcomes:
A recent phase trial of 79 adult AML cord recipients (60% DUCB), age greater than 35 years, poor-risk cytogenetics, AML not in remis-
identified a low 2-year NRM incidence of 20%, suggestive of progress sion, and lack of well-matched donors. A prognostic score could
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in this metric. In general however, current clinical practice envisages stratify outcomes from 5-year OSs of 50% (zero risk factors) to 4%
use of UCB transplantation in younger adults with high-risk AML (four risk factors). 46
in CR1 who lack suitable HLA-matched donors. Molecular genotyping offers insights into the clinical heterogene-
ity of s-AML. In a seminal analysis, Lindsley et al identified eight
genes specifically mutated in s-AML (SRSF2, SF3B1, U2AF1, ZRSR2,
Haploidentical Donors SXL1, EZH2, BCOR, STAG2) that also identify worse prognosis in
“de-novo” elderly patients with AML, likely indicating undiagnosed
There is insufficient data on haploidentical transplantation to allow antecedent MDS. They also identified a molecular signature of “de-
a precise recommendation for patients with AML. Several strategies novo” type AML. Finally, they confirmed that patients with TP53
have been used in high-risk patients, and the outcomes are encourag- mutations comprised a distinct set of AML with the worst outcomes.
ing. 3,36–38 Haploidentical transplantation is particularly interesting Molecular risk stratification offers the potential to redefine the clinical
given the potential enhancement of GVL activity by natural killer diagnosis of s-AML, refine AML risk prognostication, and potentially,
cells and allogeneic T cells responding to the HLA disparity. Regimens better select remission-inducing and postremission therapy. 47
incorporating posttransplantation cyclophosphamide for the preven-
tion of GVHD after haploidentical transplantation have gained
increasing prominence, with low rates of treatment-related mortality Acute Myeloid Leukemia in Older Adults
and GVHD. 39–41 For AML/MDS, a retrospective analysis found no
significant differences between outcomes of matched unrelated (n = AML incidence rises with age, with a median age at diagnosis of 67
108) and haploidentical (n = 32) donor HSCT with posttransplanta- years (Surveillance, Epidemiology and End Results data: http://
tion cyclophosphamide. 42 seer.cancer.gov/). For AML patients older than 60 years, consolida-
tion chemotherapy is unlikely to be curative (Fig. 61.2). Even after
adjusting for increased incidence of poor prognosis features like
Relapsed, Refractory, and Induction-Failure Acute adverse cytogenetic and molecular markers, secondary AML, comor-
Myeloid Leukemia bidities, and poorer performance status, older age remains an inde-
pendent predictor of poor survival with conventional chemotherapy.
A priori, age-related clonal hematopoiesis may be a relevant variable
Outcomes are typically poor for AML patients not in remission at for impaired survival, though this remains to be confirmed. 48,49
the time of allogeneic HSCT, although the literature in this regard is Although allogeneic HSCT is a curative therapy in the older age-
limited, heterogeneous, and likely subject to patient selection and group, there is considerable reluctance to refer these patients for
publication bias. A large analysis of MAC HSCT for acute leukemia transplantation, in contrast to younger adults with AML, in part
in relapse or in primary induction failure (including 1673 AML because of outdated assumptions regarding the tolerability of alloge-
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patients) documented a 3-year OS of 19% in AML. On multivari- neic transplantation, but also because of lack of comparative data
able analysis, risk factors at time of HSCT of poor-risk cytogenetic regarding outcomes.
AML, CR1 duration of less than 6 months, circulating AML blasts, Several reports have documented the feasibility of RIC transplan-
performance score of less than 90%, and lack of an HLA-matched tation with acceptable toxicity and reasonable survival in patients