Acute Myeloid Leukemia (AML) - Adult
Recent advances informing clinical decision-making include increasing identification of prognostic genetic markers in AML used to determine the disease risk status and a composite comorbidity/age score for treatment risk stratification. [1-7]
Because of these advances, more is known about which patients are eligible for hematopoietic cell transplantation (HCT) and which are not. In addition, large-scale studies have determined the optimal timing for HCT. As shown in Figure 1, patients with AML transplanted while in first or second complete remission have significantly better outcomes than patients transplanted with advanced disease.
Figure 1. AML Survival, Unrelated Marrow HCT, by Disease Status
Worldwide, physicians perform more than 7,000 allogeneic transplants for AML, making it the most common and fastest growing indication for allogeneic HCT. [8] As shown in Figure 2, increasing numbers of patients over age 64 years with AML are undergoing HCT, which is due to reduced-intensity conditioning regimens and better post-transplant supportive care.
Figure 2. AML Unrelated HCT, by Age
For patients with intermediate- and poor-risk cytogenetics, a meta-analysis demonstrated a survival benefit of allogeneic HCT in first complete remission over chemotherapy. [9] Early referral for HCT evaluation for these at-risk patients at an early disease stage can significantly improve survival. [10,11]
The National Marrow Donor Program® (NMDP)/Be The Match® and the American Society for Blood and Marrow Transplantation (ASBMT) have jointly developed guidelines for transplant referral timing based on disease characteristics (see Referral Timing Guidelines section below).
Disease Risk Stratification
Evolving research is altering how cytogenetic and molecular markers are used to guide therapeutic choices in AML. Table 1 shows risk status based on validated cytogenetics and molecular markers from the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia.
Table 1. European LeukemiaNet Risk Stratification By Genetics in Non-APL AML
Risk Category | Genetic Abnormality |
FAVORABLE | t(8;21)(q22;q22.1); RUNX1-RUNX1T1 inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow Biallelic mutated CEBPA |
INTERMEDIATE | Mutated NPM1 and FLT3-ITDhigh Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse-risk genetic lesions) t(9;11)(p21.3;q23.3); MLLT3-KMT2A Cytogenetic abnormalities not classified as favorable or adverse |
POOR/ADVERSE | t(6;9)(p23;q34.1); DEK-NUP214 t(v;11q23.3); KMT2A rearranged t(9;22)(q34.1;q11.2)BCR-ABL1 inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM(EVI1) -5 or del(5q); -7;-17/abn(17p) Complex karyotype, monosomal karyotype Wild-type NPM1 and FLT3-ITDhigh Mutated RUNX1 Mutated ASXL1 Mutated TP53 |
Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.1.2019, 01/18/19 © 2019 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
For patients with intermediate- and poor-risk cytogenetics, a meta-analysis demonstrated a survival benefit of allogeneic HCT in first complete remission over chemotherapy. [9] Early referral for HCT evaluation for these at-risk patients at an early disease stage can significantly improve survival. [10,11]
The National Marrow Donor Program® (NMDP)/Be The Match® and the American Society for Blood and Marrow Transplantation (ASBMT) have jointly developed guidelines for transplant referral timing based on disease characteristics (see " Referral Timing Guidelines" section below).
Advances
Recent research provides new data for the clinical management of AML:
- Molecular markers testing at diagnosis can now influence therapy choices [1-6]
- Use of the composite comorbidity/age scores (HCT-CI), instead of age alone, is useful for prognostic risk assessment before HCT [7]
- Age alone is no longer a significant factor affecting overall survival in HCT [12]
- Clinical data show a survival benefit for allogeneic HCT in Intermediate-Risk AML in first complete remission (CR1) [9]
- Increasing numbers of older patients meet eligibility requirements for allogeneic HCT because of reduced-intensity HCT [13,14]
- Survival has improved over time due to better risk stratification, supportive care, and more precise HLA matching [15,16]
- Unrelated donor transplant outcomes are similar to related donor transplant outcomes [17-19]
Outcomes
Improved Survival Over Time
Transplant outcomes have steadily improved over time, even as increasing numbers of older individuals undergo transplant (Figures 3 and 4). Review outcome data for allogeneic transplantation in adults with AML below. View additional AML slides showing demographic data and transplant trends.
Data in this section have been prepared by CIBMTR® (Center for International Blood and Marrow Transplant Research), our research program.
Figure 3: AML Survival Over Time, Unrelated HCT
Figure 4. AML Survival Over Time, Unrelated HCT
Figure 5. AML Survival, Unrelated PBSC HCT, by Disease Status
Figure 6. AML Survival, Unrelated HCT, AML patients >55 years
Figure 7. AML Survival, Sibling HCT, by Disease Status
Figure 8. AML Survival, Unrelated HCT, by Disease Status
Referral Timing Guidelines
These guidelines identify appropriate timing of consultation for transplant based on disease characteristics. [20]
Transplant Consultation Guidelines: Adult AML
High-resolution HLA typing is recommended at diagnosis for all patients
HCT consultation should take place early after initial diagnosis for all patients with AML, including:
- Primary induction failure
- Measurable (also known as minimal) residual disease after initial therapy
- CR1 - except favorable risk AML [defined as: t(8;21)(q22;q22.1); RUNX1-RUNX1T1, inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11, mutated NPM1 without FLT3-ITD, biallelic mutated
- Early referral for allogeneic HCT should be considered for any patient with AML in CR1 who is 60 years or older, regardless of cytogenetic or genomic information
- Antecedent hematological disease (e.g., myelodysplastic syndrome [MDS])
- Treatment-related leukemia
- First relapse
- CR2 and beyond, if not previously evaluated
View complete Referral Timing Guidelines
References
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- Vyas P, Appelbaum FR, Craddock C. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia. Biol Blood Marrow Transplant. 2015; 21(1): 8-15. Access
- Röllig C, Bornhäuser M, Kramer M. et al. Allogeneic stem-cell transplantation in patients with NPM1-mutated acute myeloid leukemia: Results from a prospective donor versus no-donor analysis of patients after upfront HLA typing within the SAL-AML 2003 trial. J Clin Oncol. 2015; 33(5): 403-410. Access
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- Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood. 2014; 124(23): 3441-3449. Access
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- Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: Systematic review and meta-analysis of prospective clinical trials. JAMA. 2009; 301(22): 2349-2361. Access
- Pidala J, Lee SJ, Ahn KW, et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood. 2014; 124(16): 2596-2606. Access
- Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007; 110(13): 4576-4583. Access
- McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol. 2010; 28(11): 1878-1887. Access
- Reshef R, Porter DL. Reduced-intensity conditioned allogeneic SCT in adults with AML. Bone Marrow Transplant. 2015; 50(6): 759-769. Access
- Gyurkocza B, Storb R, Storer BE, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol. 2010; 28(17): 2859-2867. Access
- Majhail NS, Chitphakdithai P, Logan B, et al. Significant improvement in survival after unrelated donor hematopoietic cell transplantation in the recent era. Biol Blood Marrow Transplant. 2015; 21(1): 142-150. Access
- Hahn T, McCarthy PL, Hassebroek A, et al. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol. 2013; 31(19): 2437-2449. Access
- Warlick ED, de Latour RP, Shanley R, et al. Allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia: Similar outcomes regardless of donor type. Biol Blood Marrow Transplant. 2015; 21(2): 357-363. Access
- Robin M, Porcher R, Adès L, et al. Matched unrelated or matched sibling donors result in comparable outcomes after non-myeloablative HSCT in patients with AML or MDS. Bone Marrow Transplant. 2013; 48(10): 1296-1301. Access
- Saber W, Opie S, Rizzo JD, et al. Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood. 2012; 119(17): 3908-3916. Access
- NMDP/Be The Match and ASBMT Recommended Timing for Transplant Consultation. Download (PDF)