Keywords non-M3 AML - decitabine - maintenance - disease-free and overall survival
Introduction
Acute myeloid leukemia (AML) is a biologically heterogeneous malignancy of the hematopoietic
stem cell (HSC). Major advances in understanding of the disease in recent years include
new knowledge about molecular pathogenesis, leading to an update of the disease classification,
technological progress in diagnostic methodologies, concept of measurable residual
disease (MRD), and successful development of newer drugs such as FLT3, IDH1, IDH2,
and BCL2 inhibitors.
The current standard of care for most patients with AML achieving a complete remission
(CR) with induction is either chemotherapy or allogeneic hematopoietic stem cell transplantation
(Allo-HSCT) depending on the genetic risk stratification of the disease.[1 ] But Allo-HSCT has its own difficulties in terms of logistics and socioeconomic challenges
in this region of our country. Again, frailty and performance status of the eligible
patients (by risk stratification) is a limiting factor for Allo-HSCT. Even after doing
Allo-HSCT and despite the incorporation of newer therapeutic modalities with intensive
chemotherapy, relapse remains a major clinical issue with relapse risk > 50% for all
adults with high-risk AML.[1 ] Given this high rate of relapse, there is urgent need to establish a postremission
maintenance therapy to mitigate the risk. Various previous studies using different
combinations of chemotherapeutic agents as postremission maintenance failed to show
a statistically meaningful improvement in overall outcome of the disease. The EORTC-HOVON
trial did not show an improvement in overall survival (OS) with low-dose cytarabine
maintenance compared with observation after remission with intensive therapy.[2 ] In the LAME 89/91 study of pediatric AML, disease-free survival (DFS) was similar
in the maintenance (18 months of monthly low-dose cytarabine 25 mg/m2 twice a day for 4 days and continuous 6-methylprednisone) and observation arms, while
OS was inferior in the maintenance arm.[3 ] Though lenalidomide has beneficial role as maintenance therapy in myeloma, it failed
to show statistically meaningful improvement in the outcome for AML.[4 ] In the realm of immune activation, immune checkpoint inhibitors have shown promising
results in Hodgkin lymphoma, Richter syndrome, and in several non hematologic malignancies,
but they have been largely disappointing as maintenance therapy in AML.[4 ] In acute lymphoblastic leukemia (ALL), maintenance has been established as a standard
of care because studies consistently show inferior outcomes in ALL without maintenance
therapy.[5 ]
There is no generally accepted definition of “maintenance therapy.” Maintenance therapy
for AML is defined by the Food and Drug Administration as an extended but time-limited
course of treatment, which is less toxic given after achievement of CR with the objective
of reducing the risk of relapse.[6 ]
Considering the continuing poor outcome of AML, there is an urgent need to explore
alternative approaches. Hypomethylating agents (HMAs) alone or in combination with
other agents have been evaluated in various international studies as maintenance strategies
in AML. Decitabine has epigenetic activity and is approved as a chemotherapeutic agent
in AML with low toxicities.[7 ] Many studies in international perspectives have used decitabine as maintenance after
remission induction with variable results. But this issue has not been addressed in
the Indian scenario. Therefore, we undertook this study to determine whether maintenance
therapy with decitabine is beneficial for patients with AML in first remission and
also to assess its side effect profiles.
Materials and Methods
Inclusion Criteria
Diagnosed non-M3 AML patients aged up to 59 years, irrespective of risk groups, not
fit/willing for Allo-HSCT
Patient fit (Eastern Cooperative Oncology Group [ECOG] 0–3) for intensive chemotherapy
Exclusion Criteria
Pregnancy
Coexisting renal and liver disease
Prior azacitidine or decitabine therapy
AML with myelodysplasia-related gene mutations or myelodysplasia-related cytogenetic
abnormalities
All adverse risk AML patients fit and opted for Allo-HSCT
Study Design
This is a prospective interventional study from May 2021 to December 2023. History
taking and clinical examination were done of all patients who were admitted in the
hematology ward with a diagnosis of AML. AML was diagnosed based on history, clinical
examination, as well as morphology and immunophenotyping of the bone marrow aspirate.
Reports of bone marrow aspiration (BMA), cytogenetics, and molecular studies were
thoroughly evaluated. Risk stratification was done according to the European LeukemiaNet
(ELN) 2017 risk category for AML. Patients were given 3 + 7 induction (cytarabine
100 mg/m2 /day continuous infusion for 7 days and daunorubicin 60 mg/m2 /day for the first 3 days). BMA was done postinduction at D28 or after count recovery
to check for disease remission status. All adverse risk group patients are counseled
for Allo-HSCT and removed from study if they chose Allo-HSCT as therapy. Other patients
in adverse risk category, not eligible for HSCT due to logistic reasons were included
in the study. Patients fulfilling the eligibility criteria received three cycles of
high-dose cytarabine (HIDAC, 3 g/m2 over 3 hours, every 12 hours, on days 1, 3, and 5). Post-third HIDAC, BMA was performed
again to check for disease remission status.
Patients remaining in CR after consolidation (3rd HIDAC) were enrolled in the study
after considering the inclusion and exclusion criteria. Informed and written consent
were obtained. Eligible patients were scheduled to receive eight cycles of decitabine
intravenously over 1 hour at 20 mg/m2 /day for 5 days, every 12 weeks. To be eligible for maintenance, patients were required
to have adequate recovery of neutrophils (> 1000/uL) and platelets (> 75000/uL) and
be within 60 days of last HIDAC.
Recovery of count is required prior to starting each subsequent cycle of decitabine.
If necessary, a 2-week delay before the next cycle of decitabine is permitted to allow
count recovery. For grade 4 neutropenia lasting more than 2 weeks or grade 4 thrombocytopenia
lasting more than 1 week after decitabine therapy, 1 day of treatment will be deleted
from the subsequent cycle. However, a minimum of 3 days of decitabine per cycle will
be required to continue protocol therapy. Patients were followed up by clinical examination,
complete blood count with peripheral blood smear, and BMA to check for disease remission
status.
Disease evaluation time points and follow-up during maintenance included bone marrow
examination every 3 months for 2 years after completion of consolidation therapy.
Expected Outcome
Primary outcomes of the study were 1-year DFS, disease relapse, and OS. Secondary
outcome were safety and tolerability of decitabine as maintenance therapy.
Criteria for Response and Toxicity
CR was defined as bone marrow cellularity ≥ 20% with absolute neutrophil count > 1 × 109 /L and platelets > 100 × 109 /L following one or two cycles of induction. The National Cancer Institute Common
Toxicity Criteria (CTCAE 5.0) were used to grade adverse events.
DFS is defined as the time from documented CR to time of relapse or death whichever
is earlier. OS is calculated as the time from study entry (i.e., prior to induction
treatment) to death from any cause. Event-free patients were censored at the time
of their last follow-up. DFS and OS are calculated using the methods of Kaplan and
Meier statistics and compared with historical control.[8 ]
Statistical Analysis
Data collected are entered in MS-Excel to make a database. JAMOVI software, version
2.6.26 (free), was used for analysis. Categorical variables are expressed as proportion
and percentage and numerical variables as mean and standard deviation. Survival is
calculated as per duration of months. DFS and OS are calculated using the Kaplan and
Meier method. For statistical significance, unpaired t -test is used. A p -value of < 0.05 is considered as statistically significant.
Ethical Approval
All procedures performed in this study involving human participants were in accordance
with the ethical standards of the institute. Ethical clearance from the Institutional
Ethics Committee has been taken bearing no. NMC/6672 dated 10/12/2019.
Results
Of the 20 patients registered for the maintenance therapeutic agent decitabine, median
age was 23.5 years (range: 4–54 years). Pediatric patients (< 18 years of age) were
six and male:female ratio was 3:1.
Seven patients were in the favorable, nine patients in the intermediate, and four
patients in the adverse risk group. According to performance status (PS), nine patients
were in PS1, seven in PS2, and four in PS3. There were six patients who were t (8::21) positive by conventional cytogenetics.
Following table shows the baseline characteristics of the patients ([Table 1 ]).
Table 1
Baseline characteristics of the study subjects (N = 20)
Baseline characteristics
Value
Age (y)
Median
Range
Pediatric patient (number)
23.5
4–54
6
Sex
Male
Female
Ratio
15
5
3:1
AML risk category
Favorable
Intermediate
Adverse
7
9
4
Performance status (PS) (ECOG)
PS1
PS2
PS3
9
7
4
Conventional cytogenetics
Normal
t (8::21)
Others
8
6
6
Abbreviations: AML, acute myeloid leukemia; ECOG, Eastern Cooperative Oncology Group.
A total of 88 cycles of decitabine were administered (mean: 4.4). Eight patients developed
hematological adverse effects ([Table 2 ])—seven patients were grade 3 and one was grade 4. No nonhematological adverse events
were noted. One patient died due to febrile neutropenia.
Table 2
Hematological adverse effects experienced by the patients (N = 20)
Grade 3 adverse events
No. of patients
Grade 4 adverse events
No. of patient
Anemia
2
Anemia
0
Neutropenia
3
Neutropenia
1
Thrombocytopenia
2
Thrombocytopenia
0
Note: According to the Common Toxicity Criteria for Adverse Events (CTCAE) Version
5.
The median follow-up of the surviving patients was 29 months (range: 8–30 months).
For the entire treated subjects (n = 20), the median OS was 27.5 months with a 30 months' survival rate of 80%. The median DFS in the group was 20.5 months. Corresponding
survival curve (Kaplan–Meier) is shown in [Figs. 1 ] and [2 ].
Fig. 1 Overall survival of the patients (N = 20).
Fig. 2 Disease-free survival of the patients (N = 20).
The median OS in pediatric patient was 19.5 months as compared with 28.5 months in
adults, while median DFS in pediatric patient was 18.5 months as compared with 24
months in adults (p = 0.628 for both). Women (n = 5) were observed to have median OS and DFS of 30 and 23 months, respectively, whereas
men (n = 15) had OS of 22 months and DFS of 18 months (p = 0.303 for both). Mean DFS and OS of the historical control groups were 18.4 and
23.8 months, respectively.[8 ]
Discussion
It has been shown by previous studies that HMA is well tolerated and has activity
as single agent and in combinations in AML and myelodysplastic syndrome, which was
the basis for the present study. Therefore, we considered maintenance treatment with
decitabine after intensive induction chemotherapy to be a potentially interesting
option, especially for patients in CR who are not eligible or fit for Allo-HCT. Furthermore,
the azacitidine, due to its hypomethylating mechanism, after conventional chemotherapy,
has antileukemic effects that are additive to the effects of chemotherapy. Few studies
provided knowledge about the clonal hierarchy and they identified preleukemic HSCs
in remission samples, which may survive after exposure to chemotherapy. This concept
supports the use of azacitidine and decitabine as maintenance agents in AML.[9 ] But the beneficial effects of long-term maintenance therapy in AML have not been
conclusively established till date. Decitabine and azacitidine may be useful to maintain
the remission in AML patients.
Previous studies with HMA are presented below in tabular forms ([Table 3 ]).[10 ]
[11 ]
[12 ]
[13 ]
[14 ]
[15 ]
[16 ]
Table 3
Previous studies with HMA as maintenance in AML
Name of study
Study design
Outcome
ECOG-ACRIN (E-A) E2906 trial[10 ]
120 patients of ≥ 60 years with a diagnosis of AML in remission were randomized to
decitabine (20 mg/m2 for 3 days each 4-week cycle for 1 year) or observation after intensive therapy
At a median follow-up period of 50 months after the start of induction therapy, there
was no statistically significant difference in DFS or OS between the two arms
CALGB 10503 phase 2 trial[11 ]
Patients of AML remained in CR postinduction and consolidation were given eight cycles
of decitabine IV over 1 hour at 20 mg/m2 /day for 5 days, every 6 weeks for 1 year
For the group that received maintenance decitabine, 1-year DFS and OS were 79% and
96%, respectively. Decitabine maintenance did not provide any apparent benefit for
DFS or OS relative to the historical reference group
A single-arm MRD-based study from MD Anderson Cancer Center (MDACC)[12 ]
31 patients with CBF-AML received maintenance decitabine
The investigators concluded that decitabine can be an effective maintenance for CBF-AML
patients with persistent low level MRD after FLAG-based induction regime
HOVON trial: Phase 3 RCT[13 ]
112 patients ≥ 60 years with AML/MDS-excess blasts in CR/CRi after intensive therapy
were randomized to receive azacitidine (50 mg/m2 for 5 days, every 4 weeks for a maximum of 12 cycles) or observation
DFS was significantly improved in the therapy arm (12-month DFS: 64% vs. 42%; p = 0.04) with no difference in OS
QUAZAR AML-001 trial: phase 3, randomized, double-blind, placebo-controlled trial
of the oral formulation of azacitidine[14 ]
AML patients ≥ 55 years in remission following chemotherapy and not candidate for
HSCT were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14
days per 28-day cycle
Median OS was significantly longer with CC-486 than with placebo (24.7 and 14.8 months,
respectively). Median RFS was also significantly longer with CC-486 than with placebo
and the benefit were shown in most subgroups defined according to baseline characteristics
AML-342, A Phase II Study of azacitidine and venetoclax as maintenance therapy in
AML[15 ]
This is a phase 2, single-center, single-arm study ongoing since 9/2019. Azacitidine
50 mg/m2 IV/SQ ×5 days and venetoclax 400 mg ×14 days or 7 days were administered in 28-day
cycles, up to 24 cycles
Out of 34 patients, 9 relapsed and 6 died. The median RFS and OS were not reached.
Most common grade ¾ adverse events were thrombocytopenia and neutropenia
GOELMAS trial: Phase II multicentric trial[16 ]
117 poor-risk AML patients in CR after intensive induction received 12 maintenance
cycles alternating every 28 days AZA (sc 75 mg/m2 /d1–7) and Len (10 mg/d1–21)
Median follow-up for survivors was 38 months (26–47). Median OS was 10 months, with
21% 2-year OS. Median CR duration was 7 months (1–30)
Abbreviations: AML, acute myeloid leukemia; AZA, azacitidine; CBF, core binding factor;
CR, complete remission; CRi, incomplete count recovery; DFS, disease-free survival;
FLAG, fludarabine, cytarabine, G-CSF; HMA, hypomethylating agent; HSCT, hematopoietic
stem cell transplantation; IV, intravenous; Len, lenalidomide; MDS, myelodysplastic
syndrome; MRD, measurable residual disease; OS, overall survival; RCT, randomized
controlled trial; RFS, relapse-free survival; SQ, subcutaneous.
In this prospective interventional study, 20 newly diagnosed AML patients in morphological
CR after induction and three cycles of consolidation were given maintenance decitabine
at 12 weeks' intervals and followed up. Median DFS and OS were 20.5 and 27.5 months,
respectively. Adult patients had better outcome compared with the pediatric group,
though statistically insignificant. The most common hematological adverse event in
the entire cohort was neutropenia. One patient died of febrile neutropenia.
In our study, we have included newly diagnosed patients of AML irrespective of the
ELN 2017 risk category similar to other previously mentioned studies like the ECOG-ACRIN,
CALGB 10503, HOVON, and QUAZAR AML-001 trials. This is supported by the fact that
core binding factor AML (CBF-AML), despite inclusion in favorable risk category, relapse
is a major concern with leukemia-free survival remains at 50 to 60%.[17 ] In the CALGB 10503 trial described, a sizeable percentage of patients (34%) had
CBF-AML and even in them, non-MRD-directed decitabine maintenance did not seem to
improve DFS or OS.[11 ] In another single-arm study from the MDACC, 31 patients with CBF-AML treated with
fludarabine-based I-C regimen, decitabine was administered as a maintenance agent
in those who had persistent MRD positivity by quantitative polymerase chain reaction
or who failed to receive all planned cycles of consolidation. Among 23 patients with
MRD at the initiation of maintenance, 12 (52%) attained complete molecular response
with a median molecular relapse-free survival of 93 months.[12 ]
Again, it was not possible from our study to derive which risk category of patients
benefitted most from decitabine maintenance owing to less sample size. In the ECOG-ACRIN
(E-A) E2906 trial, investigators found there was a significant impact on OS for the
FLT3-ITD-negative population, apart from improved OS in the decitabine arm compared
with observation. In the HOVON trial, though there is improvement in DFS in the azacitidine
arm compared with observation (64% vs. 42%), OS did not differ between various treatment
groups. Similarly, in other studies also, it could not be conclusively asserted about
the most benefitted group according to the molecular risk category.
Conclusion
Outcome of the present study in terms of DFS and OS is comparable or little better
compared with the historical control with the reservation of small sample size and
absence of control arm. Further studies are needed with larger sample size and longer
follow-up period with a control arm to elucidate the effectiveness of decitabine as
maintenance agent in AML after attaining first CR.
