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Patients with acute myeloid leukemia (AML) who are refractory to standard chemotherapy regimens have a poor prognosis. For patients with acute lymphoblastic leukemia (ALL), despite recent advances with novel targeted therapies, long-term outcomes remain poor due to relapse and resistance. Salvage allogeneic hematopoietic stem cell transplantation (HSCT) is a common option for these patients but is only curative in approximately 10–15% of patients, highlighting the need for novel, more efficacious transplantation approaches.
In a pre-clinical study, the substitution of post-transplant cyclophosphamide (PTCy) with post-transplant bendamustine (PTB) led to comparable graft-versus-host-disease (GvHD) control and significantly augmented graft-versus-leukemia (GvL) effect. However, the preventative effect of PTB alone and its optimal dosing are unknown. Moiseev et al.1 investigated PTB alone and in combination with other immunosuppressive agents for GvHD prophylaxis in patients with relapsed/refractory leukemia. The GvHD Hub is pleased to summarize the key findings here.
A prospective, open-label, phase I/II dose-ranging study of PTB in patients with refractory acute leukemia (NCT02799147). Patients with AML, ALL, or mixed lineage acute leukemia were eligible if primary or secondary refractory to at least one course of induction or immunotherapy, had >5% of clonal blasts in bone marrow (BM) or peripheral blood, had an available sibling, 8–10/10 human leukocyte antigen (HLA) matched-unrelated, or haploidentical donor, and had a Karnofsky performance score (KPS) ≥70%.
All patients (N = 27) received myeloablative conditioning therapy (as shown in Figure 1) followed by allocation to either 70, 100, or 140 mg/m2 of PTB. The first 12 patients received only PTB, while the remaining 15 patients received a combination therapy with tacrolimus and mycophenolate mofetil (MMF) from Day +5. No other relapse prophylaxis therapy was permitted; however, pre-emptive therapy for measurable residual disease (MRD) was allowed.
Figure 1. Dosing schedule*
PTB, post-transplantation bendamustine.
*Adapted from Moiseev et al.1
†Enrollment halted at seven patients due to three consecutive cases of non-relapse mortality.
The median age of patients was 38 years (range, 20–56) and the median blast count in BM was 18% (range, 6–97) (as shown in Table 1). Of the patients, 22 had AML and five had ALL. At least one HLA-mismatch was seen in 15 donors, whereas the remaining 12 donors were 10/10 HLA-matched. The median KPS was 80% (range, 70–90), and 24 patients had a first allograft, two had a second, and one had a third allograft. Excess iron was seen in a significant number of patients at the time of HSCT.
Table 1. Baseline characteristics*
Characteristic |
N = 27 |
---|---|
Male/Female, % |
48/52 |
Median age, years (range) |
38 (20–56) |
Diagnosis, % |
|
Graft source, % |
|
CD34+ cells, × 106/kg cells, mean ± SD |
6.2 ± 2.0 |
Refractory disease, % |
|
Previous induction therapies, median (range) |
2 (1–7) |
Median serum ferritin level, ng/mL (range) |
1,200 (48–3,828) |
Median blast count in BM, % (range) |
18 (6–97) |
Karyotype, % |
|
Donor, % |
|
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BM, bone marrow; PBSC, peripheral blood stem cell. |
No differences were observed in the incidence of severe CRS (p = 0.795) or in severity of CRS (p = 0.642) between patients receiving PTB alone or in combination with tacrolimus and MMF.
In total, 89% patients achieved a complete response (CR) and 63% had MRD-negative remission. A higher proportion of the patients with AML (71%) were MRD negative compared with patients with ALL (40%). Table 2 shows the OS, EFS, NRM, and relapse incidence for all patients.
Table 2. OS, EFS, NRM, and relapse incidence*
Outcome |
Patients, % (95% CI) |
---|---|
3-year OS |
28 (13–46) |
EFS |
29 (13–46) |
NRM |
46 (25–64) |
Cumulative incidence of relapse |
26 (11–44) |
AML, acute myeloid leukemia, CI, confidence interval; EFS, event-free survival; NRM, non-relapse mortality; OS, overall survival. |
The adverse events (AEs) were as expected for patients with AML and ALL (see Table 3). The most common causes of mortality were progressive disease (22%) and CRS-related deaths (22%).
Table 3. Adverse events*
Grade 3–4 AEs, % |
Patients |
---|---|
Mucositis |
30 |
AE, adverse event; CMR, cytomegalovirus reactivation; TATM, transplant-associated thrombotic microangiopathy. |
This study demonstrates that PTB could be a potential GvHD prophylactic treatment for supplementing the GvL effect in refractory AML. The complications of developing severe cGvHD after single-agent PTB therapy with the use of HLA-matched allografts can be controlled with a combination of PTB with tacrolimus and MMF starting on Day +5. However, PTB cannot be used without additional immunosuppression even in the low-risk GvHD population, such as recipients of matched-related BM transplantation, due to high rate of CRS.
Future studies are therefore needed to investigate CRS and effectiveness of PTB in a larger sample using patients with ALL.
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