Page 1101 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 61 Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome in Adults 971

TABLE European LeukemiaNet AML Risk Classification 10 It constitutes the largest risk category, accounting for approximately
61.1 40–50% of adult AML patients less than 60 years of age. Long-term
disease-free survival of approximately 40–45% is anticipated after
Genetic Group Subsets consolidation chemotherapy. However, identification of mutations
Favorable t(8;21)(q22;q22); RUNX1-RUNX1T1 with prognostic importance such as mutant FLT3 internal tandem
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); duplication (FLT3-ITD), nucleophosmin 1 (NPM1), and CEBPA
CBFB-MYH11 (CCAAT/enhancer binding protein-α) can help further individualize
Mutated NPM1 without FLT3-ITD (normal the decision regarding allogeneic transplantation.
karyotype) Patients with FLT3-ITD have inferior survivals compared with
10,11
Mutated CEBPA (normal karyotype) those without FLT3-ITD. The negative impact of FLT3-ITD
appeared abrogated by allogeneic transplantation in CR1 when
Intermediate-I a Mutated NPM1 and FLT3-ITD (normal karyotype) assessed on an ITT donor versus no-donor basis, although in this
Wild-type NPM1 and FLT3-ITD (normal analysis the patients were not preferentially assigned transplantation
karyotype) on this basis. In an updated analysis, the FLT3-ITD mutant level
Wild-type NPM1 without FLT3-ITD (normal appeared relevant to AML prognosis and HSCT benefit, with high
karyotype)
levels (AR ≥0.51) associated with lower CR rates and poor survival.
Intermediate-II t(9;11)(p22;q23); MLLT3-MLL Importantly, these patients benefit from allogeneic HSCT, while
Cytogenetic abnormalities not classified as those with low FLT3-ITD mutant levels clinically behave similarly
favorable or adverse b to those without FLT3-ITD. The NPM1 and CEBPA mutations
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Adverse inv(3)(q21q26.2) or t(3;3)(q21;q26.2); are associated with good outcomes independent of HSCT, and most
10,12–14
RPN1-EVI1 investigators do not offer HSCT in first remission. The favor-
t(6;9)(p23;q34); DEK-NUP214 able impact of NPM1 mutations appears to persist even in older
t(v;11)(v;q23); MLL rearranged patients, although this belief is in evolution, and allogeneic HSCT
15–17
−5 or del(5q); −7; abnl(17p); complex karyotype c may be a consideration in older AML There is a growing list
of additional prognostic markers undergoing evaluation in AML.
a Includes all AMLs with normal karyotype except for those included in the
favorable subgroup; most of these cases are associated with poor prognosis. These include mutation analysis of RAS, WT1, RUNX1, MLL,
b For most abnormalities, adequate numbers have not been studied to draw firm TET2, IDH1/2, TP53; expression levels of individual genes like
conclusions regarding their prognostic significance. EVI1, ERG, MN1, and BAALC; and gene expression and microribo-
c Three or more chromosome abnormalities in the absence of one of the WHO nucleic acid (miRNA) profiling. 6,10,16 In a large analysis to develop
designated recurring translocations or inversions, that is, t(15;17), t(8;21),
inv(16) or t(16;16), t(9;11), t(v;11)(v;q23), t(6;9), inv(3) or t(3;3) a prognostic model for AML based solely on molecular markers,
Grossmann et al documented five distinct AML prognostic subtypes:
(1) very favorable: PML-RARA rearrangements or CEBPA double
mutations (3-year OS: 82.9%); (2) favorable: RUNX1-RUNX1T1,
CBFB-MYH11, or NPM1 mutation without FLT3-ITD (3-year
Prognostic Factors for Acute Myeloid Leukemia in OS 62.6%); (3) intermediate: none of the mutations leading to
First Complete Remission assignment in the other groups (3-year OS: 44.2%); (4) unfavorable:
MLL-PTD and/or RUNX1 mutation and/or ASXL1 mutation (3-year
OS: 21.9%); and (5) very unfavorable: TP53 mutation (3-year OS:
Good-Risk Acute Myeloid Leukemia 0%). If validated, such analyses highlight the ability of molecular
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markers to further delineate prognosis within AML, especially within
In general, the 15% to 20% of AML patients with core binding factor intermediate-risk AML. This suggests that this category of risk will
(CBF) leukemia—t(8;21) (q22;q22) and inv(16)(p13.q22)—are gradually disappear as prognostic precision improves. Although the
considered to have good-risk disease, with a long-term disease-free better-prognosis subgroup within intermediate-risk AML may not
survival of approximately 50–60% after consolidation chemotherapy, benefit from early allogeneic transplantation, HSCT appears to
and allogeneic HSCT is not routinely recommended for patients be the preferred postremission therapy for intermediate-risk AML
achieving CR1. However, retrospective studies have identified activat- patients at higher risk for relapse, including those lacking favorable
ing mutations in C-KIT (mKIT)—a member of the type III receptor gene mutations like NPM1 without FLT3-ITD, or double mutant
tyrosine kinase family—at exon 17 (mKIT 17) or exon 8 (mKIT 8) CEBPA. With the advent of mutation analysis an interesting question
in approximately 30% of CBF AMLs that are associated with will be whether patients in remission but with detectable clonal
increased relapse incidence and likely poorer survival, though results hematopoiesis are better served going to HSCT despite the good-risk
8,9
from individual studies vary. For instance, in an analysis of 61 cytogenetics.
patients with inv(16), mKIT was associated with 5-year relapse rate
of 56% compared with 29% (p = .05) without mKIT mutations. This
effect is especially prominent with mKIT17, where 80% relapsed Poor-Risk Acute Myeloid Leukemia
compared with 29% without the mutation (p = .002). Similarly, in
49 patients with t(8;21), the 5-year relapse rate was 70% in the In poor-risk AML relapse rates are high and survival rates are antici-
presence of mKIT mutations compared with 36% with wild-type pated to be 15% or lower with conventional therapy. Allogeneic
mKIT (p = .017). These relapse rates are similar to that of poor-risk HSCT with a matched sibling or unrelated donor results in long-term
AML, suggesting a potential benefit of allogeneic HSCT in this survival of 30–40% and is considered the treatment of choice for
subset. Importantly, relative mutant level (mutant/wild-type allelic adults less than 60 years of age with poor-risk AML. There is,
ratio [AR]) may also be relevant, with a retrospective analysis of however, a subgroup of poor-risk AML that may have particularly
prospective AML trials suggesting the negative prognostic impact of adverse prognosis, for whom additional novel therapeutic strategies
mKIT in CBF AML is restricted to cases with AR ≥0.25. 10 may be necessary.
The monosomal karyotype (MK) is defined by the presence
of a single autosomal monosomy, in association with at least one
Intermediate-Risk Acute Myeloid Leukemia additional monosomy or non–good-risk structural chromosomal
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abnormality (i.e., excluding CBF mutation AML). In the original
The intermediate-risk cytogenetic group is heterogeneous and report, MK-positive AML patients had a long-term survival of only
includes cytogenetically normal disease as well as those with karyo- 3–4%, and these generally dismal chemotherapeutic outcomes have
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typic abnormalities not meeting criteria for good- or poor-risk AML. been confirmed by other investigators. Allogeneic transplantation