1.Clinical data: There were 6 males and 3 females with a median age of 71 (65-82) years old. The PS scores were ≥2. Among them, two patients had secondary recurrence, two patients had their first recurrence, and five patients had AML with myelodysplastic related changes (AML-MRC). Eight patients had at least one cycle of AZA or combined with low-dose chemotherapy before the application of VEN; 3 patients had TP53 gene mutation, of which 2 patients had complex chromosome karyotype (see table 2); 1 patient had FLT3-ITD gene mutation, 3 patients had DNMT3A mutation, 2 patients had IDH2 mutation, 1 patient had TET2 mutation, 3 patients had RUNX1 mutation and 1 patient had U2AF1 mutation.
Table 2. Clinical characteristics of patients
Patient no.
|
Age
(years)
|
Gender
|
WHO diagnosis
|
ECOG,PS
scores
|
Blast Percentage (%)
|
WBC(*109/L)
|
HB(g/L)
|
PLT(*109/L)
|
LDH level (IU/L)
|
Mutated gene
|
Cytogenetics
|
Complications
|
Respose
|
0S
|
Cytogenetic response?
|
1
|
69
|
F
|
AML-M5
(second relapse)
|
2
|
14
|
0.9
|
80
|
65
|
144
|
CEBPA NPM1、TET2、TP53、DNMT3A
|
46,XX
|
hypertension、diabetes、
Hypothyroidism
|
CR3
|
≥16
|
Yes
|
2
|
71
|
F
|
AML-M2
(second relapse)
|
2
|
7.5
|
1.88
|
130
|
134
|
113
|
IDH2
|
46, XX
|
coronary heart disease
|
CR3
|
≥13
|
Yes
|
3
|
74
|
M
|
AML-MRC
|
3
|
20.5
|
3.45
|
51
|
263
|
317
|
ASXL1、BCOR、RUNX1、IDH2
|
46, XY
|
none
|
CR1
|
≥15
|
Yes
|
4
|
82
|
M
|
AML-MRC
|
3
|
21
|
4.62
|
82
|
25
|
312
|
TP53、DNMT3A
|
46,XY, add(4)(p16), del(5)(q21), del(7)(q31), +8,del(16)(q22)
|
hypertension
|
CRi
|
11
|
Yes
|
5
|
71
|
M
|
AML-MRC
|
3
|
20
|
1.83
|
72
|
2
|
129
|
RUNX、U2AF1、FLT3-ITD
|
46, XY
|
coronary heart disease;Coronary stenting
|
No response
|
-
|
No
|
6
|
65
|
F
|
AML-MRC
|
3
|
37
|
1.3
|
65
|
298
|
473
|
IDH1、NPM1
CEBPA、DNMT3A
|
46, XX
|
hypertension、diabetes、postcholecystectomy
|
Not evaluable
|
-
|
No
|
7
|
69
|
M
|
AML-MRC
|
2
|
2.5
|
5.38
|
118
|
159
|
152
|
TP53
|
45,XY,-5,add(11)(p15),add(13)(p11),add(15)(p11),-17,-18, -20,+22,
|
hypertension、diabetes、
|
CR1
|
7
|
No
|
8
|
68
|
M
|
AML-MRC(relapse)
|
2
|
18
|
2.04
|
124
|
81
|
240
|
RUNX1
SRSF2
IDH1
BCOR
ASXL1
SETBP1
KMT2A
TET2
|
47,XY,+8
|
Severe pulmonary infection
|
CR2
|
≥3
|
Yes
|
9
|
65
|
M
|
AML-MRC(relapse)
|
2
|
13
|
5.48
|
157
|
83
|
182
|
ASXL1
SRSF2
GATA2
|
46,XY
|
diabetes
|
CR2
|
≥5
|
Yes
|
2. Adverse Events: Gastrointestinal reactions: 6/9 patients had mild nausea, no vomiting. Hematologic toxicity: Granulocytopenia occurred in 8/9 patients during the first two cycles of treatment, of which 5 patients developed severe infections.One patient died of severe neutropenia and septic shock. Thrombcytopenia occurred in 5/9 patients, of which 2 patients developed severe bleeding and died. There was no obvious tumor lysis syndrome in nine patients.(see table.3)
Table.3
Adverse Events
|
Hematologic toxicity
|
Gastrointestinal reactions
|
Tumor lysis syndrome
|
Granulocytopenia
|
Thrombcytopenia
|
Nausea
|
Vomiting
|
No.1
|
yes
|
no
|
slight
|
no
|
no
|
No.2
|
yes
|
no
|
slight
|
no
|
no
|
No.3
|
yes,skin and soft tissue infectiongs,staphylococcemia
|
no
|
no
|
no
|
no
|
No.4
|
yes,pneumonia
|
yes
|
slight
|
no
|
no
|
No.5
|
yes, pseudomonas aeruginosa
|
Yes,gastrointestinal bleeding
|
slight
|
no
|
no
|
No.6
|
Yes,stenotrophomonas maltophilia pneumonia
|
Yes,abdominal hemorrhage
|
slight
|
no
|
uncertain
|
No.7
|
no
|
yes
|
no
|
no
|
no
|
No.8
|
yes
|
no
|
slight
|
no
|
no
|
No.9
|
Yes,fungal pneumonia
|
yes
|
no
|
no
|
no
|
3.Therapeutic effect: Except case 6 died in the early stage and the therapeutic effect could not be evaluated ,6 patients among the remaining 8 patients had efficacy with the response rate (CR/CRi) at 75%, which occurred around the time when the regimen was given for 1.5 cycles(1-3cycles).
In case 1, the course of AML was 4 years. At the time of initial diagnosis, due to biallelic mutated CEBPA and mutated NPM1 without FLT3-ITD, the risk stratification was low-risk. At that time, standard induction therapy, medium and large dose of cytarabine consolidation, and intensive therapy were given, and the mutation gene was corrected after therapy. One year later, the patient relapsed for the first time, with mutations of TET2, TP53 (VAF=4.55%) and DNMT3A genes. The patient was treated with low-dose chemotherapy containing another HMA, decitabine, and bone marrow obtained CR again. The second complete remission lasted for one year. Aside from the TET2 gene, TP53, DNMT3A, and NPM1 gene mutations occurred again in the second relapse, which was not relieved after 2 cycles of azacytidine treatment alone. The third CR (CR3) was achieved after 2 cycles of AZA+VEN treatment, and NPM1 mutation was corrected again.
Case 2 was initially diagnosed as a moderate risk patient. Standard induction chemotherapy and intensive treatment with high dose cytarabine was used in a consolidation period. After 6 years of long-term remission, azacytidine combined with low-dose cytarabine induction treatment was effective in obtaining CR2 after the first relapse occurred. During single drug azacytidine maintenance treatment, the patient relapsed again with IDH2 gene mutation. Because an IDH2 inhibitor was not available, AZA+VEN treatment was administered, and CR3 was obtained after one cycle of treatment. The IDH2 gene mutation was corrected after two cycles.
Case 3 was diagnosed as AML-MRC with ASXL1, BCOR, RUNX1 and IDH2 gene mutations. According to the National Comprehensive Cancer Network (NCCN) guidelines, azacytidine with 75mg/m2/d monotherapy was the first line choice. After four cycles of treatment, the proportion of bone marrow blast cells failed to decrease, and the patient had to continuously receive the transfusion of red blood cells. Therefore, the evaluation of curative effect was invalid and the paitne became a refractory case. After adjusting to AZA+VEN, CR1 was obtained after two cycles of treatment, and the mutation gene BCOR was resolved. These three patients received a combined VEN therapy after ineffective single drug azacytidine treatment, and achieved CR.
Case 4 was an elderly patient with complex karyotype with 7q- and TP53 gene mutation. Three factors including elder, complex karyotype, and TP53 mutation were independent adverse prognostic factors (13). Therefore, AZA combined with VEN induction therapy was given. CRi was obtained after one course of treatment, and the VAF of TP53 decreased from 41.4% to 2.06%.
Cases 5 and 6 were both initially diagnosed as MDS-EB2. After a course of single drug azacytidine treatment, the disease progressed to AML-MRC, and severe neutropenia occurred after the addition of venetoclax. The former case developed Pseudomonas aeruginosa, which improved after antibiotic treatment. But after another course of AZA+VEN treatment, there was no improvement and the patient died of gastrointestinal bleeding because of thrombocytopenia for long time
Case 6 developed neutropenia, Pseudomonas maltophilia infection and primary resistance to carbapenems. On the 14th day after treatment with AZA+VEN, the patient died of severe pulmonary infection.
Case 7 was diagnosed as AML-MRC with complex karyotype and TP53 mutation(VAF is 58.1%). Although CR1 was obtained by azacytidine combined with low dose cytarabine, the VAF value of TP53 gradually increased from 6.3% to 11.8% during consolidation treatment, suggesting that this case would be refractory to the therapies and the prognosis would be poor. After three cycles of combined therapy using AZA+VEN, the VAF value of TP53 increased from 11.8% to 28%. Thrombocytopenia occurred more than 2 weeks after the fourth cycle treatment and died of abdominal hemorrhage.
Cases 8 and 9 were both diagnosed as AML-MRC and were treated with AZA and low-dose cytarabine when relapsed. After VEN be added for only one cycle, CR2 was obtained. In case 8, there were seven genes mutation when relapsed, including RUNX1, SRSF2, IDH1, ASXL1, SETBP1, KMT2A, TET2. When 2 cycles treatment finished, the mutation genes RUNX1, , IDH1, ASXL1 and SETBP1 were resolved. There were three genes mutation including ASXL1, SRSF2 and GATA2 when relapsed in case 9 and only GATA2 mutation retained after two cycles treatment.