Page 388 - Williams Hematology ( PDFDrive )

362 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 363

cell disease were published in 2014 by EBMT. In patients with hemo- in CR1. There are no prospective, genetically randomized trials in older
233
globin disorders, transplantation serves as a form of gene therapy, using adults with AML comparing allogeneic HCT to chemotherapy in CR1,
allogeneic hematopoietic cells as vectors for genes essential for normal but retrospective comparisons suggest that allogeneic HCT can reduce
hematopoiesis. Eventually the vector may well be autologous stem cells relapse risk and improve outcomes in this demographic. 244,245 The deci-
transformed by the insertion of normal genes. 234 sion to proceed to allogeneic HCT in older adults is often based less on
For patients with SCID syndrome and other congenital immuno- disease risk factors and more on medical comorbidities and the esti-
deficiencies, allogeneic HCT remains the treatment of choice. 235,236 The mated risk of TRM, which may be prohibitive.
role of allogeneic HCT for patients with storage diseases, a diverse group In the genomic era of AML risk stratification, patients with inter-
of disorders that typically involve a single gene defect in a lysosomal mediate-risk disease are often categorized based on the results of molec-
hydrolytic enzyme or peroxisomal function, is evolving and it appears ular testing for mutations of FLT3, NPM1, and CEBPA. Patients with
that subsets of mucopolysaccharidoses derive the most benefit. 237 intermediate-risk cytogenetics and biallelic CEBPA mutations or NPM1
mutations in the absence of FLT3 mutations have good-risk disease
246
and are often not considered for allogeneic HCT in CR1. In contrast,
SELECTED RESULTS OF HEMATOPOIETIC patients with internal tandem duplications in FLT3 have poorer prog-
CELL TRANSPLANTATION noses and are often considered for allogeneic HCT in CR1.
Detailed guidelines have been published by the European Leu-
A comprehensive discussion of transplantation outcomes is beyond the kemiaNet AML Working Party to guide the use of allogeneic HCT in
scope of this chapter; please refer to other disease-focused chapters of this AML patients in CR. Based on existing data, many experts would
247
text for more complete information. A brief overview of transplantation- recommend allogeneic HCT for all medically fit patients younger than
related outcomes in a number of diseases is presented here. 60 years old with AML in CR1 except for those with favorable-risk dis-
ease (including those with intermediate-risk cytogenetics and favorable
Acute Myeloid Leukemia molecular markers) who achieve CR1 with their first cycle of induction
Allogeneic HCT has a major role in the management of patients with and have no evidence of minimal residual disease. For all other younger
AML. For patients in CR1, the decision to proceed to allogeneic HCT as CR1 patients—including those with intermediate-risk cytogenetics and
opposed to chemotherapy-based consolidation is predicated on prog- negative molecular markers, and those in any cytogenetic risk group
nostic markers and donor availability, as well as patient preference. For who do not promptly achieve CR with induction or who have minimal
patients beyond CR1, allogeneic HCT often offers the only potentially residual disease—allogeneic HCT should be strongly considered as the
248
curative treatment option. best postremission option. For older adults with AML in CR1, allo-
First Complete Remission A question of significant practical geneic HCT should be considered for all medically fit patients except
importance is how best to treat a younger AML patient who achieves those with favorable-risk disease, although there are fewer data to sup-
a CR1 following induction chemotherapy. Several large prospective tri- port this recommendation and medical comorbidities play an increas-
als have been conducted using so-called genetic randomization: that is, ingly important role in decision making as patients age.
patients in CR1 with an HLA-identical sibling received allogeneic HCT, The role of consolidation chemotherapy before allotransplantation
while those without an HLA-identical sibling received chemother- in patients in CR1 is unclear. Many transplant physicians recommend
apy-based consolidation or autologous HCT. 238,239 Two meta-analyses at least 1 to 2 cycles of consolidation, especially for patients slated to
have focused on the comparative outcomes of allogeneic HCT versus receive RIC, in order to maximize pretransplantation cytoreduction.
chemotherapy, both of which found that allogeneic HCT in CR1 yielded However, two recent retrospective studies have questioned the benefit
better overall and disease-free survival for patients with intermedi- of consolidation chemotherapy, and instead favored moving forward
ate- and poor-risk cytogenetics, but not for those with favorable-risk to allogeneic HCT as soon as a suitable donor is available. 249,250 Con-
cytogenetics. 240,241 For patients with poor-risk cytogenetics, there is lit- solidation chemotherapy is to maintain remission during prolonged
tle dispute that allogeneic HCT is the preferred postremission therapy donor searches, but its benefit is less clear in patients who have a donor
for medically fit patients with available donors. Conversely, patients identified.
younger than 60 years of age with favorable-risk cytogenetics who Aml Beyond First Complete Remission For patients with AML
promptly achieve CR1 with induction chemotherapy are generally not who relapse after attaining a CR1, allogeneic HCT is the treatment of
considered for allogeneic HCT, and instead should receive chemother- choice. While no prospective randomized trials have compared alloge-
apy-based consolidation. For younger patients with intermediate-risk neic HCT to salvage chemotherapy alone in this setting, retrospective
251
cytogenetics, allogeneic HCT in CR1 from an HLA-identical sibling data strongly support the use of allogeneic HCT. Autologous HCT
donor is the best available postremission therapy, but its advantage over has been used historically in patients who lacked suitable allogeneic
252
other approaches is not as substantial as in the setting of poor-risk cyto- donors, but with the advent of improved alternative-donor options the
genetics. One caveat is that the studies demonstrating the superiority use of autologous HCT for AML has become rare except in developing
of allogeneic HCT were performed using genetic randomization, and countries without the capability to perform allogeneic HCT. Patients with
thus the results are, strictly speaking, only applicable to patients with AML beyond CR1 who lack suitably HLA-matched donors are candi-
HLA-identical sibling donors. That said, single-center and registry data dates for HLA-haploidentical or UCB allotransplantation, as retrospec-
suggest that outcomes with HLA-matched unrelated donor allotrans- tive studies have associated these approaches with equivalent overall and
plantation for AML in CR1 are similar to those with HLA-identical disease-free survival compared to allotransplantation from conven-
sibling donors, 242,243 so it is reasonable to extrapolate the results of the tional donor sources. 253,254
genetic-randomization studies to patients with HLA-matched unrelated The likelihood of long-term survival is very low in AML patients
donors. whose disease fails to achieve CR1 following induction therapy
Patients older than 60 years of age typically have substantially (primary induction failure) and in those whose disease is chemorefrac-
higher relapse rates with chemotherapy alone (60 to 80+ percent) 244,245 tory at relapse. Allogeneic HCT with myeloablative conditioning has
and have poorer outcomes than younger patients with equivalent cyto- been reported to cure approximately 19 to 30 percent of such patients
genetics, suggesting that older adults may benefit from allogeneic HCT in retrospective analyses. 192,255 These retrospective reports undoubtedly

Kaushansky_chapter 23_p0353-0382.indd 363 9/19/15 12:47 AM