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C H A P T E R 61

ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

FOR ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC

SYNDROME IN ADULTS

John Koreth, Joseph H. Antin, and Corey Cutler

Recent advances in molecular diagnostics are shedding consider- analysis from the European Society for Blood and Marrow Trans-
able light on genetic underpinnings of myelodysplastic syndrome plantation, the ability to use donors that are not histocompatible will
(MDS) and acute myeloid leukemia (AML). However, with notable further increase the pool of patients in whom HSCT is an effective
exceptions both diseases remain therapeutic challenges. Fortunately therapy. 3,4
our ability to provide more precise prognostic information has
corresponded with advances in transplantation technology. We are
increasingly able to apply transplantation to older people and those Matched Related Donor HSCT for Adult Acute Myeloid
with comorbidities and to use alternative donors in patients without Leukemia in First Complete Remission
matched family members. By applying molecular prognostic criteria
we can provide transplantation to patients with poor outcomes on Currently cytogenetics remains the most powerful prognostic
conventional therapy, and we can avoid transplant-related toxicity indicator in AML, both at the time of diagnosis and at relapse,
in those patients who are likely to do well with supportive care or and can also direct choice of curative postremission therapy, espe-
5,6
nontransplant therapy. cially for adult patients less than 60 years of age. Adult AML
Allogeneic hematopoietic stem cell transplantation (HSCT) patients can be stratified into good-risk, intermediate-risk, and
is curative in MDS and AML because of a combination of the poor-risk groups on the basis of numeric and/or structural chro-
cytotoxicity of the preparative conditioning regimen and the donor- mosomal abnormalities and the presence of specific mutations (see
mediated immunologic graft-versus-leukemia (GVL) effect. Regimen Chapter 58). Increasingly molecular genotyping supplements, and
intensity ranges from high-dose myeloablative conditioning (MAC) may ultimately supplant, karyotype-based AML prognostication.
that induces profound and prolonged pancytopenia to reduced- For instance, current European LeukemiaNet consensus incorpo-
intensity conditioning (RIC) that induces milder cytopenias and is rates molecular mutations to derive AML prognostic risk groups
more appropriate for older patients and those with comorbidities in (Table 61.1). 7
whom MAC may be intolerable. The risk-benefit ratio of condition- Numerous groups have evaluated prospectively the relative benefits
ing regimen intensity varies with factors like patient age, comorbidi- of allogeneic HSCT versus nonallogeneic therapies (consolidation
ties, and relapse risk. In general, more intense regimens cause more chemotherapy or autologous HSCT) in adult AML patients 18 to 60
treatment-related morbidity and mortality but are associated with a years of age in first complete remission (CR1). Treatment allocation
lower relapse rate. Conversely, there are more relapses in RIC HSCT, was by biologic assignment as a surrogate for true randomization, with
but the procedure is more tolerable. 1 allogeneic HSCT for patients with available human leukocyte antigen
(HLA)–matched sibling donors (donor group) and nonallogeneic
consolidation for those lacking matched sibling donors (no-donor
ACUTE MYELOID LEUKEMIA group). Some studies further stratified postremission outcomes by
cytogenetic risk. Individual studies, when analyzed on an intent-to-
AML displays clinical heterogeneity with markedly variable survival, treat (ITT) donor versus no-donor basis, typically demonstrated that
traditionally defined by prognostic factors of patient age, white blood allogeneic HSCT was effective at improving disease-free survival,
cell count, prior MDS or cytotoxic therapy, remission status, and but overall survival benefit was hard to document because of graft-
karyotype, but increasingly further refined by its molecular heteroge- versus-host disease (GVHD) and other treatment-related mortality.
neity. In addition to new prognostic indicators, there are now novel Moreover, transplantation in CR2 salvages some of the patients who
AML therapeutic agents in clinical trials, which also constitute an relapsed, thus making overall survival (OS) similar with the two
alternative to conventional cytotoxic chemotherapy and are poten- approaches.
tially intercalatable with HSCT. A meta-analysis of over 6000 patients in 24 biologic treatment
However, AML also constitutes the leading indication for HSCT assignment trials, however, confirmed that OS was in fact better in
worldwide, and accounts for 20,905 of 61,825 allogeneic transplants allogeneic matched related donor transplantation in AML-CR1, with
(34%) in the United States and reported to the Center for Inter- a hazard ratio (HR) of death at 0.90 (95% confidence interval [CI],
7
national Blood and Marrow Transplant Research (CIBMTR) in the 0.82 to 0.97). Importantly, when stratified by cytogenetic risk, there
decade 2003–13 (M. Pasquini, personal communication). Moreover, was an OS benefit of allogeneic transplantation (Table 61.2) for both
the use of molecular tissue typing in conjunction with better control intermediate-risk (HR, 0.83; 95% CI, 0.74 to 0.93) and poor-risk
of treatment-related complications has increased the use of alternative (HR, 0.73; 95% CI, 0.59 to 0.90) cytogenetic groups, but not for
donors. Data from the CIBMTR indicate that 1286 of 1778 allo- good-risk AML-CR1 (HR, 1.07; 95% CI, 0.83 to 1.38) (Fig. 61.1).
geneic HSCT (72%) undertaken for AML in 1998 involved related These findings were particularly relevant for patients with normal
donors, compared with 1223 of 2557 allogeneic HSCT (48%) cytogenetic AML, who constitute the largest subgroup and for whom
in 2008. In contrast, the number of unrelated donor HSCT for no consensus regarding optimal postremission treatment was previ-
adult AML increased from 297 in 1998 to 1017 in 2008, while the ously available. These studies did not, however, have the benefit of
number of umbilical cord blood (UCB) transplantations increased prognostic assignment based on FLT3, NPM1, or other molecular
2
from 11 to 130 over the same time period. As shown in a recent markers.
970