Azacitidine in Combination With or Without All-trans Retinoic Acid in Newly Diagnosed Unfit Acute Myeloid Leukemia or Intermediate,High or Very High Risk Myelodysplastic Syndromes (MDS) as Per IPSS-R Criteria
Phase: PHASE2
Conditions: AML, MDS, Old Age; Debility, Hematologic Cancer
Sponsor: The First Affiliated Hospital of Soochow University

Azacitidine With or Without All-trans Retinoic Acid for Newly
Diagnosed Acute Myeloid Leukemia or Intermediate,High or Very
High Risk Myelodysplastic Syndromes Unfit for Intensive
Chemotherapy
Vision 3.0
December. 22
2021
ClinicalTrials.gov Identifier:
Principal Investigator Yue Han, MD, PhD, hanyue@suda.edu.cn; Depei Wu, MD, PhD,
wudepei@suda.edu.cn. Jiangsu Institute of Hematology, The First Affiliated Hospital of
Soochow University, Suzhou 215006, China.

Background
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are common
clonal malignant diseases that originate from hematopoietic stem cells. A part of AML and
intermediate，high or very high risk MDS patients cannot tolerate intensive chemotherapy
due to the age and poor physical condition, resulting in limited overall survival.
Nowadays, hypomethylating agents （HMA) such as azacytidine(AZA) are recommended as
first-line therapy for acute myeloid leukemia or myelodysplastic syndromes patients unfit for
intensive chemotherapy
[1,2]. Previous studies have shown that the CR rate and ORR of AZA in
the treatment of adverse-risk MDS patients are 9
~13
and 30
~34
respectively [3-6].
HMA combined with all-trans retinoic acid (ATRA) can up-regulate tumor suppressor gene
P16 and RARβ, down-regulate oncogene WT1, and cooperatively inhibit leukemia cell
proliferation , induce apoptosis and differentiation
［7-9］.
Thirty-one elderly patients with myeloid tumor who could not tolerate the intense
chemotherapy were treated with low-dose DAC combined with ATRA to achieve a Good
curative effect. The CR rate was 22.6 , mCR was achieved in 7 cases (22.6 ), PR was achieved
in 4 cases (12.9
), ORR was 58.1
and the median OS was 11 months
[10]. A multicenter
clinical trial on the treatment of elderly patients with newly diagnosed AML showed that the
median ORR of 35 patients treated with decitabine plus ATRA was 26.1 and a median OS of
8.4 months
[11]. These results suggest that HMA combined with ATRA may achieve better
efficacy in patients who are not suitable for intensive chemotherapy.
In order to improve the prognosis and survival of newly diagnosed AML and MDS
patients who are not eligible for intensive induction chemotherapy, we intend to conduct a
prospective study to investigate the efficacy and safety of HMA combined with ATRA in
newly diagnosed AML and intermediate/adverse risk MDS patients who are not eligible for
intensive chemotherapy, and to explore the related mechanism of action.
Research purpose
This is a randomized, open-label, multi-center clinical trial. This study aims
to to
compare the efficacy and safety of AZA with or without ATRA in newly diagnosed unfit AML
or Intermediate, High or Very High Risk MDS patients who can not tolerate intensive
chemotherapy.
Study design
1.
Patients meeting the criteria were enrolled according to inclusion and exclusioncriteria.
2.
The patients who meet the criteria for enrollment are randomly assigned 1:1.
3.
Estimated Enrollment:
180 participants.
Inclusion Criteria:

1.Chinese guidelines for the diagnosis and treatment of acute myeloid
leukemia (2021 edition)，excludesacute promyelocytic leukemia (M3、APL)
and Intermediate, High or Very High Risk myelodysplastic
syndromes(2019 edition)
2.Be at least 18 years of age on day of signing informed consent.
3.Not suitable for newly diagnosed patients with intensivechemotherapy.
4.Not suitable for newly diagnosed patients with receivinghematopoietic
stem cell transplantation
5.The proportion of blast cells was below 50% in bone marrow
6.Total white blood cell (WBC) count ≤10,000/µL；
Exclusion Criteria:
1.Malignant neoplasms with other progression
2.Serious mental illness uncooperative
3.Refusal to join the study
Research scheme and Experimental diagram
Experimental Group A:
Azacytidine 75mg/m2/d by IV on days 1-7 of every cycle ATRA 20mg tid by po 1-21 day of
every cycle 28 days
Experimental Group B:
Azacytidine 75mg/m2/d by IV on days 1-7 of every cycle 28 days
Assess disease status: In the course of treatment, if the proportion of blast cells in the patient
increased compared with the initial diagnosis, indicating the disease progression. Patients
with disease progression were dropped out of the study, and other patients continued with
the original regimen. After 6 courses of treatment, experimental group A maintenance
therapy: ATRA 20mg tid by po 1-21 day of every cycle for 1 year，azacytidine 75mg/m2/d
by IV on days 1-7 every 3 months for 1 year. The disease should be assessed again after 3
cycles. If the disease progressed, the patient should be withdrawn from the study.
experimental group B maintenance therapy: azacytidine 75mg/m2/d by IV on days 1-7 every
3 months for 1 year.
Study
process
Screening phase

Demographic data: age, sex, nationality, address, spouse's characteristics, contact
information.
Physical
examination:
height,
body
weight,
blood
pressure,
body
temperature, heart rate, body surface area, respiratory and cardiovascular system

examination, nervous system examination, hepatosplenomegaly, Eastern Cooperative
Oncology Group (ECOG) score, etc.

Laboratory
examination:
Blood
analysis:
blood
routine
test,
blood
biochemistry,
coagulation function and cardiac biomarker. BM examination: marrow morphology
examination, flow cytology, chromosome, gene mutation; Immune function test:
humoral immunity, T lymphocyte subsets, NK cells, cytokines;
Treatment period (28 days for a cycle)

Drugs will be given based on the protocol;

Blood routine test once a day, coagulation function test and blood biochemistryare
performed twice a week, respectively;

T Cellular Subjects and NK cells, cytokines are performed after treatment.

Bone marrow examination: Bone puncture was reviewed after every course of treatment
for AML and three course for MDS, and the treatment response was evaluated
according to the 2020 NCCN guidelines and the Chinese Guidelines for diagnosis and
Treatment of Myelodysplastic syndrome (2019 edition) and Chinese guidelines for the
diagnosis and treatment of myelodysplastic syndromes(2017 edition) ;

Important vital signs are recorded.

Adverse events will be recorded and managed according to this protocol.
Primary Outcome Measure
1.Overall Response Rate （ORR)[ Time Frame: Up To 6 Months ]
Number of participants (responders) achieving ORR (CR+PR+HI) after the 6
cycle treatments
2.Overall survival (OS) [ Time Frame: Up To 24 Months ]
OS is defined as the number of days from the date of randomization to the date of death of
any cause, or last known date to be alive.
3.Progression-free survival (PFS) [ Time Frame: Up To 24 Months ]
Progression-free survival (PFS) will be measured from time of enrolling in the clinical trial
to the date on which disease progresses or the date on which the patient dies, whichever
comes first.
Secondary Outcome Measures:
1. Percentage of Participants Achieving Transfusion Independence (TI) Who are
Transfusion Dependent at Baseline [ Time Frame: Up To 6 months ]TI is when the
participants who were transfusion dependent on RBC and/or Platelet at baselineachieve
transfusion independence post baseline. TI is a period of at least 56 days with no
transfusion after the date of the first dose of study drug to the last dose of study drug +
30 days, the initiation of post-treatment therapy, or death, whichever is earliest.
2. Incidence of systemic infections [ Time Frame: Up to 6 months ]
Follow-up phase
All study patients should be followed up until the end of the study to obtain the data of
survival.Follow-up time: Patients who completed treatment should be monitored 24 months
after the start of the study and 6 months after the completion of treatment. During the
follow-up
period
after
treatment,
blood
routine,
peripheral
blood
morphology
and
biochemistry were monitored every 12 weeks until the study end point. Follow up the
treatment and prognosis of the patients who withdrawal from clinical trials until the end
point of study.
Reference
1.
Chinese Society of Hematology, Chinese Medical Association. [Chinese guidelines for
diagnosis and treatment of myelodysplastic syndromes (2019)]. Zhonghua Xue Ye Xue Za Zhi.
2019 Feb 14;40(2):89-97.
2.
Leukemia & Lymphoma Group, Chinese Society of Hematology,
Chinese Medical
Association. [Chinese guidelines for diagnosis and treatment of adult acute myeloid leukemia (not
APL) (2017)]. Zhonghua Xue Ye Xue Za Zhi. 2017 Mar14;38(3):177-182.
3.
Dombret H，Seymour JF，Butrym A，et a1．International phase 3 study of azaeitidine vs
conventional care regimens in older patients with newly diagnosed AML with>30 ％
blasts[J]．Blood，2015，126(3)：291—299．DOI：10．1 182／blood．2015-01-621664.

4.
Delia M，Carluecio P，Buquicchio C，et a1．Azaeitidine in the reatment of older patients
affected by acute myeloid leukemia：A report by the Rete Ematologica Pugliese(REP)[J]．Leuk
Res,2015DOI:10.10166.1eukres.2015.08.005，
5. Fenauxp ，Muftigj ，Hellstorm Lindberge ，etal ．Efficacyof azacitidine compared with that
of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a
randomised ，open-label ，phase Ⅲstudy［J］．Lancet Oncol ，2009,10(3):223-232.
6.
Pappav，Anagnostopouso，Bouronikoue，etal ．Aretrospective study of azacitidine treatment
in patients with intermediate- ２or high risk myelodysplastic syndromes in a real-world clinical
setting in Greece［J］．Int J Hematol ，2017,105(2),:184-195.
7. Xiang L，Zhou J，Gu W，et al. Changes in expression of WT1during induced differentiationof
the acute myeloid leukemia celllines by treatment with 5-aza-2'-deoxycytidine and all-trans
retinoic acid［J］. Oncol Lett，2016，11（2）:1521-1526.
8.Xiang L，Wang R，Wei J，et al. Retinoic acid receptor-beta gene reexpression and biological
activity in SHI-1 cells after combined treatment with 5-aza-2'- deoxycytidine and all-trans retinoic
acid［J］. Acta Haematol，2015，133（3）：279-286.
9.Xiang L，Dong W，Wang R，et al. All-trans retinoic acid enhances the effect of 5-aza-2' -
deoxycytidine on p16INK4a demethylation ，and the two drugs synergistically activate retinoic
acid receptor beta gene expression in the human erythroleukemia K562 cell line［J］. OncolLett，
2014，8（1）：117-122.
10. Wu W，Lin Y，Xiang L，et al. Low-dose decitabine plus alltrans retinoic acid in patients with
myeloid neoplasms ineligiblefor intensive chemotherapy［J］. Ann Hematol，2016，95（7）：
1051-1057.
11.Lübbert M, Grishina O, Schmoor C, et al. Valproate and Retinoic Acid in Combination With
Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter,
Randomized, 2 × 2, Phase II Trial. J Clin Oncol. 2020;38(3):257-270.