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Myeloablative conditioning (MAC) has been used in the eradication of disease and to prolong long-term survival, and is successful in approximately 50% of younger patients with acute myeloid leukemia (AML). However, this treatment modality is associated with a high rate of non-relapse mortality (NRM); therefore, FLAMSA (fludarabine, Ara-C, and amsacrine) chemotherapy (CT) followed by reduced-intensity conditioning (RIC) is being investigated as an effective and safer alternative in this setting.
Rodríguez-Arboli and colleagues1 recently published a comparative reassessment of FLAMSA-based RIC vs MAC in Biology of Blood and Marrow Transplantation. Their aim was to ascertain the best supportive care that contributes to decreasing NRM rates. This was a registry-based analysis by the Acute Leukemia Working Party (ALWP), part of the European Society for Blood and Marrow Transplantation (EBMT).
Patients eligible for this study were aged 18–50 years, were primary refractory, had relapsed AML at least twice with active disease at the time of transplant, had their first allogeneic hematopoietic stem cell transplant (allo-HSCT) from a matched sibling donor (MSD) or an unrelated donor (UD) between 2005–2018, and had received MAC with cyclophosphamide and total body irradiation (Cy/TBI), busulfan/cyclophosphamide (Bu/Cy), or FLAMSA-RIC (which includes both FLAMSA-CT and FLAMSA-TBI). Patients were excluded if they received oral busulfan and/or ex-vivo T-cell depleted allografts.
The study endpoints were overall survival (OS), relapse incidence (RI), leukemia-free survival (LFS), non-relapse mortality (NRM), acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), and refined GvHD-free, relapse-free survival (GRFS).
This analysis was conducted with 1,018 patients for a median follow-up of 50 months. The patient, disease, and transplant characteristics are shown in Table 1.
Table 1. Patient characteristics1
AML, acute myeloid leukemia; Ara-C, cytosine arabinoside; A, amsacrine; Bu, busulfan; CsA cyclosporine; CT, chemotherapy; Cy, cyclophosphamide; FLAMSA, fludarabine + Ara-C + amsacrine; GvHD, graft-versus-host disease; IQR, interquartile range; MAC, myeloablative conditioning; MMF, mycophenolate mofetil; MSD, matched sibling donor; MTX, methotrexate; TBI, total body irradiation; UD, unrelated donor * Bu dosing was 6.4 mg/kg and 12.8 mg/kg in the FLAMSA-CT and MAC groups, respectively. |
||||
|
FLAMSA-CT |
FLAMSA-TBI |
MAC |
p |
|
(n = 128) |
(n = 318) |
(n = 572) |
|
Median follow-up, months (IQR) |
24.5 (15–41) |
58.1 (16–94) |
65.0 (17–107) |
< 0.0001 |
Median year of transplant |
2015 |
2010 |
2010 |
< 0.0001 |
Median age at transplant, years (range) |
41.6 (18.6–50) |
39.7 (18.1–50) |
37.3 (18.1–49.9) |
0.002 |
AML type, n (%) |
0.546 |
|||
De novo |
113 (88.3) |
279 (87.7) |
515 (90) |
|
Secondary |
15 (11.7) |
39 (12.3) |
57 (10) |
|
Disease status at transplant, n (%) |
0.604 |
|||
Primary refractory |
62 (48.4) |
170 (53.5) |
297 (51.9) |
|
First relapse |
57 (44.5) |
127 (39.9) |
224 (39.2) |
|
Second relapse |
9 (7.0) |
21 (6.6) |
51 (8.9) |
|
Donor type, n (%) |
< 0.001 |
|||
MSD |
31 (24.2) |
94 (29.6) |
223 (39) |
|
UD |
97 (75.8) |
224 (70.4) |
349 (61) |
|
Conditioning scheme, n (%) |
||||
Bu/Cy* |
68 (53.1) |
— |
258 (45.1) |
|
Cy/TBI |
— |
— |
314 (54.9) |
|
Bu |
18 (14.1) |
— |
— |
|
Melphalan |
22 (17.2) |
— |
— |
|
Cy |
7 (5.5) |
— |
— |
|
Treosulfan |
8 (6.3) |
— |
— |
|
Cy/Treosulfan |
5 (3.9) |
— |
— |
|
GvHD prophylaxis, n (%) |
||||
CsA/MMF |
92 (71.9) |
231 (73.3) |
45 (8.0) |
|
CsA/MTX |
5 (3.9) |
8 (2.5) |
413 (73.6) |
|
MMF/tacrolimus |
15 (11.7) |
14 (4.4) |
6 (1.1) |
|
CsA |
7 (5.5) |
17 (5.4) |
54 (9.6) |
|
MMF/sirolimus |
2 (1.6) |
22 (7.0) |
0 |
The authors highlight potential limitations of the study, including the possible introduction of selection bias during the allocation of treatment as it was dependent on center preference.
The team go on to highlight that this study is the largest comparative analysis of clinical outcomes in patients who received MAC or FLAMSA-RIC with active AML. The results show that patients who received FLAMSA-TBI had an NRM rate similar to those treated with MAC. In all analyses, there were no differences in terms of antileukemic activity. These data support the use of FLAMSA-CT as a conditioning regimen in patients with active relapsed or refractory AML due to lower NRM, though the high relapse rates highlight the need for novel therapeutics and warrant further research.
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