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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the few curative options for patients diagnosed with acute myeloid leukemia (AML).1 Transplantation can be performed after first relapse or in the first complete remission (CR) period if a patient’s relapse risk is deemed high enough to outweigh the risk of non-relapse mortality. It is also a viable option for patients who achieve a second CR period after relapse.1 To further refine pre-treatment assessment, a large proportion of patients who undergo HSCT in the first CR are intermediate or adverse genetic risk according to the European LeukemiaNet (ELN) 2017 risk classification. Measurable residual disease (MRD) assessment has increasingly become part of the evaluation process prior to treatment and has allowed clinicians to assess a patient’s response to different therapy options with greater precision.1
Jentzsch et al. recently published a study in Blood Advances that evaluated the currently used genetic risk stratification models and MRD status in predicting patient outcomes when performing HSCT in the first or second remission periods.1 We summarize the findings below.
A total of 580 patients diagnosed with AML who had their first allo-HSCT between January 1999 and November 2020 were retrospectively evaluated. Cytogenetic analysis was performed at diagnosis, including the mutation status of CEBPA, NRM1, and internal tandem duplication (ITD) in FLT3 (FLT3-ITD). Assessment of MRD was performed up to 28 days before HSCT using remission samples. The median follow-up time was 3.9 years.
The median age at HSCT was 59.6 years, with 72% of patients having received nonmyeloablative or reduced-intensity conditioning, and 28% myeloablative conditioning. Patients undergoing HSCT in the second CR or CR with incomplete peripheral cell count recovery (CRi) period (n = 120), compared with patients transplanted in first CR/CRi (n = 460), had an increased likelihood of the following:
Patients who underwent HSCT in the second CR/CRi also had elevated levels of hemoglobin (p = 0.01), white blood cell counts (p = 0.006), and bone marrow blasts (p = 0.03) when compared with baseline levels. On the other hand, patients in this group had a lower likelihood of having a monosomal or complex karyotype. Furthermore, fewer cycles of chemotherapy were administered prior to HSCT to patients in their second CR/CRi, who also more often received grafts from human leukocyte antigen (HLA)-mismatched donors compared with patients in their first CR/CRi receiving other types of grafts. Full patient characteristics are shown in Table 1.
Table 1. Patient characteristics*
All patients |
HSCT in first CR/CRi |
HSCT in second CR/CRi |
p value |
|
---|---|---|---|---|
Characteristics at diagnosis |
||||
Sex, n (%) |
0.68 |
|||
Male |
308 |
242 (53) |
66 (55) |
|
Female |
272 |
218 (47) |
54 (45) |
|
Disease origin, n (%) |
0.002 |
|||
Secondary/treatment-related AML |
195 |
169 (37) |
26 (22) |
|
De novo AML |
385 |
291 (63) |
94 (78) |
|
Hemoglobin, g/dL, median (range) |
8.9 (3.2–15.7) |
8.7 (3.2–15.7) |
9.5 (4.3–14.9) |
0.01 |
WBC, ×109/L, median (range) |
5.9 (0.1–385) |
5.4 (0.1–385) |
17.1 (0.6–366) |
0.006 |
BM blasts, %, median (range) |
51 (0–95) |
50 (0–95) |
61 (22–95) |
0.03 |
ELN 2017 risk group, n (%) |
0.15 |
|||
Favorable |
112 |
89 (25) |
23 (34) |
|
Intermediate |
147 |
123 (34) |
24 (36) |
|
Adverse |
168 |
148 (41) |
20 (30) |
|
Normal karyotype, n (%) |
<0.001 |
|||
Absent |
288 |
253 (59) |
35 (34) |
|
Present |
247 |
178 (41) |
69 (66) |
|
Complex karyotype, n (%) |
<0.001 |
|||
Absent |
445 |
346 (84) |
99 (100) |
|
Present |
67 |
67 (16) |
0 (0) |
|
Monosomal karyotype, n (%) |
<0.001 |
|||
Absent |
459 |
359 (87) |
100 (98) |
|
Present |
58 |
56 (13) |
2 (2) |
|
NPM1, n (%) |
0.03 |
|||
Wild type |
328 |
280 (77) |
48 (65) |
|
Mutated |
108 |
82 (23) |
26 (35) |
|
FLT3-ITD, n (%) |
<0.001 |
|||
Wild type |
345 |
298 (81) |
47 (63) |
|
Mutated |
96 |
68 (19) |
28 (37) |
|
CEBPAbiallelic, n (%) |
0.08 |
|||
Wild type |
344 |
292 (99) |
52 (95) |
|
Mutated |
7 |
4 (1) |
3 (5) |
|
Characteristics at HSCT |
||||
Median age at HSCT, years (range) |
59.6 (16.3–76.8) |
60.3 (16.3–76.0) |
59.6 (19.2–76.8) |
0.43 |
Treatment cycles prior to HSCT, n (%) |
<0.001 |
|||
1 |
157 |
72 (16) |
85 (71) |
|
2 |
311 |
280 (61) |
31 (26) |
|
≥3 |
111 |
107 (24) |
4 (3) |
|
Blood count regeneration at HSCT, n (%) |
0.41 |
|||
CR |
484 |
387 (84) |
97 (81) |
|
CRi |
96 |
73 (16) |
23 (19) |
|
MRD status at HSCT, n (%) |
0.10 |
|||
MRD− |
167 |
133 (58) |
34 (47) |
|
MRD+ |
133 |
95 (42) |
38 (53) |
|
Donor type, n (%) |
0.02 |
|||
Matched related |
124 |
109 (24) |
15 (13) |
|
Unrelated, HLA matched |
329 |
258 (56) |
71 (59) |
|
HLA mismatched |
112 |
80 (17) |
32 (27) |
|
Haploidentical |
14 |
12 (3) |
2 (2) |
|
AML, acute myeloid leukemia; BM, bone marrow; CR, complete remission; CRi, complete remission with incomplete peripheral cell count recovery; ELN, European LeukemiaNet; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplantation; ITD, internal tandem duplication; MRD, measurable residual disease; WBC white blood cell. |
Patients transplanted in the second CR/CRi period recorded a significantly higher cumulative incidence of relapse (CIR; p < 0.001) and shorter relapse-free survival (RFS; p = 0.002) compared with patients receiving HSCT in the first CR/CRi. However, overall survival (OS) and non-relapse mortality were similar in both groups. Multivariable analysis revealed the number of remissions remained a significant prognostic factor for CIR and RFS (both p < 0.001), although not for OS, following adjustment for ELN 2017 genetic risk and the MRD status at HSCT. Moreover, for patients undergoing HSCT in the first CR/CRi, more intensive conditioning regimens were associated with better OS (p < 0.001). In contrast, patients in the second CR/CRi who remained in remission for longer than 1 year before first relapse demonstrated lower CIR (p < 0.001) and longer RFS (p = 0.001).
In both groups of patients, MRD positivity prior to HSCT was a significant prognostic factor for higher CIR (both groups, p < 0.001) and shorter RFS (first CR/CRi, p = 0.002; second CR/CRi, p = 0.04,). However, OS was similar across patients who were MRD positive or MRD negative who underwent HSCT in first or second CR/CRi.
The distribution of ELN genetic risk groups was similar between patients transplanted in first and second remission. However, in all risk groups, patients who received HSCT in second remission had a higher CIR compared with patients transplanted in first remission. The frequency of ASXL1, RUNX1, and TP53 mutations were similar across each of the risk groups.
Transplantation during second remission was associated with a higher risk of relapse than in the first remission, regardless of ELN genetic risk. The authors also noted that, within the group of patients with ELN intermediate genetic risk, MRD positivity had a great prognostic value, with patients who were MRD positive and underwent transplantation during the second remission having the poorest outcomes. They therefore recommended avoiding transplantation in these patients.
Limitations to this study included its retrospective nature and the lack of data availability, in particular MRD status during chemotherapy and post-HSCT.
Although MRD status at HSCT still remains highly relevant, therapies targeting specific molecular aberrations should be considered prior- and post-HSCT, especially in the group of patients who are MRD positive and in second remission, in order to improve outcomes.
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