Abstract

Introduction

The hypomethylating agent 5-azacytidine (AZA) has been the standard of care for higher risk Myelodysplastic Syndromes (MDS) for the last few years. Its efficacy has been proven in large clinical trials, and its safety has been shown to be superior to that of conventional treatments. We have conducted a retrospective study about the efficacy and safety of 5-azacytidine, as reported and analyzed in our center.

Patients and Methods

Forty four consecutive patients with MDS or Acute Myeloid Leukemia (AML) with 20-30% bone marrow blasts that were treated with AZA during the last 63 months were included in the study. The clinical and laboratory characteristics of the patients were recorded, and the efficacy and safety data were analyzed.

Results

The epidemiologic and hematologic characteristics of the patients are shown in Table 1. The median overall survival was 13 months (1-101) and there was no primary treatment failure (Table 2). Serious adverse events consisted mostly of neutropenic infections (blood stream and pneumonia) (Table 3).

Discussion

Treatment with AZA offered a favorable (complete and partial) response in 34.1% of the patients, and an overall survival of 13 months, with generally predictable toxicities, although hospitalization was frequently inevitable during the first treatment cycles, when supportive treatment was a significant part of the management. A valuable observation is that there was a considerable decrease in the patients’ transfusion needs following treatment (p<0.0001). Our results are consistent with the results of other clinical trials and point out the need for investigational 5-azacytidine combinations.

Table 1.

Epidemiologic and hematologic characteristics.

Male: Female ratio30:14 (2.1 : 1)
Age, Median (Range) 73 (54-81) 
WHO classification of MDS/AML, N (%)
RAEB-I
RAEB-II
RCMD-RS
RCMD
RARS
CMML
AML 
9 (20.5)
18 (40.9)
2 (4.5)
3 (6.7)
1 (2.3)
4 (9.1)
7 (15.9) 
IPSS classification, N (%)
Low
Intermediate-1
Intermediate-2
High
Not Applicable (AML) 
0 (0)
3 (6.8)
29 (65.9)
5 (11.4)
7 (15.9) 
Complete Blood Count Parameters, Median (Range)
Hemoglobin (g/dL)
Absolute Neutrophil Count (x109/L)
Platelet count (x109/L) 
8.55 (4.5 - 12.5)
1.08 (0.0 – 16.3)
80.0 (2 – 820) 
Transfusion dependence, N (%) 39 (88.6) 
Transfusions per month, Median (Range) 3 (0 – 7) 
Male: Female ratio30:14 (2.1 : 1)
Age, Median (Range) 73 (54-81) 
WHO classification of MDS/AML, N (%)
RAEB-I
RAEB-II
RCMD-RS
RCMD
RARS
CMML
AML 
9 (20.5)
18 (40.9)
2 (4.5)
3 (6.7)
1 (2.3)
4 (9.1)
7 (15.9) 
IPSS classification, N (%)
Low
Intermediate-1
Intermediate-2
High
Not Applicable (AML) 
0 (0)
3 (6.8)
29 (65.9)
5 (11.4)
7 (15.9) 
Complete Blood Count Parameters, Median (Range)
Hemoglobin (g/dL)
Absolute Neutrophil Count (x109/L)
Platelet count (x109/L) 
8.55 (4.5 - 12.5)
1.08 (0.0 – 16.3)
80.0 (2 – 820) 
Transfusion dependence, N (%) 39 (88.6) 
Transfusions per month, Median (Range) 3 (0 – 7) 

Table 2.

Efficacy data

AZA cycles, Median (Range)5 (1-22)
Actual AZA dose (mg/m2/cycle), Median (Range) 75 (59-75) 
Actual cycle duration (days), Median (Range) 28 (28-40) 
Dose reductions due to sustained neutropenia, N (%) 6 (13.6) 
Temporary AZA interruption, N (%) 26 (59.1) 
Reason  
Sustained cytopenia 10/26 (38.5) 
Neutropenic Infection 15/26 (57.7) 
Hemorrhagic Complication 1/26 (3.8) 
Permanent AZA discontinuation, N (%) 23/44 (52.3) 
Reason  
AML transformation 17/23 (73.9) 
Recurrent or severe infection 4/23 (17.4) 
Pyoderma gangrenosum 1/23 (4.3) 
Allogeneic Bone Marrow Transplantation 1/23 (4.3) 
AZA cycles till response (according to the IWG criteria), Median (Range) 4 (1 – 7) 
Response (IWG criteria), N (%)
Complete response
Partial response
Stable disease
Failure 
7 (15.9)
8 (18.2)
29 (65.9)
0 (0) 
Overall survival (months), Median (Range) 13 (1 – 101) 
Post treatment transfusion dependence, N (%) 34 (77.3) 
Transfusions per month (post-treatment), Median (Range) 1 (0 – 5) 
Death rate, N (%) 29/44 (65.9) 
Cause of death, N (%)
Infection
Hemorrhage
Cardiac dysrhythmia 
24/29 (82.8)
3/29 (10.3)
2/29 (6.9) 
AZA cycles, Median (Range)5 (1-22)
Actual AZA dose (mg/m2/cycle), Median (Range) 75 (59-75) 
Actual cycle duration (days), Median (Range) 28 (28-40) 
Dose reductions due to sustained neutropenia, N (%) 6 (13.6) 
Temporary AZA interruption, N (%) 26 (59.1) 
Reason  
Sustained cytopenia 10/26 (38.5) 
Neutropenic Infection 15/26 (57.7) 
Hemorrhagic Complication 1/26 (3.8) 
Permanent AZA discontinuation, N (%) 23/44 (52.3) 
Reason  
AML transformation 17/23 (73.9) 
Recurrent or severe infection 4/23 (17.4) 
Pyoderma gangrenosum 1/23 (4.3) 
Allogeneic Bone Marrow Transplantation 1/23 (4.3) 
AZA cycles till response (according to the IWG criteria), Median (Range) 4 (1 – 7) 
Response (IWG criteria), N (%)
Complete response
Partial response
Stable disease
Failure 
7 (15.9)
8 (18.2)
29 (65.9)
0 (0) 
Overall survival (months), Median (Range) 13 (1 – 101) 
Post treatment transfusion dependence, N (%) 34 (77.3) 
Transfusions per month (post-treatment), Median (Range) 1 (0 – 5) 
Death rate, N (%) 29/44 (65.9) 
Cause of death, N (%)
Infection
Hemorrhage
Cardiac dysrhythmia 
24/29 (82.8)
3/29 (10.3)
2/29 (6.9) 

Table 3.

Safety data

Clinical adverse events, N (%)29/44 (65.9)
Neutropenic Infections 26/29 (89.7) 
Bloodstream Infection 9/26 (34.6) 
Lower respiratory infection 10/26 (38.5) 
Neutropenic Fever 8/26 (30.1) 
Septic shock 2/26 (7.7) 
Hemorrhagic events 2/29 (6.7) 
Cerebral hemorrhage (Grade 5) 1/2 (50.0) 
Epistaxis (Grade 3) 1/2 (50.0) 
Other (pyoderma gangrenosum) 1/29 (3.4) 
Laboratory incidents1, N (%) 44/44 (100) 
 All grades Grades 3/4 
Neutropenia 36/44 (81.8) 34/44 (77.3) 
Anemia 44/44 (100) 24/44 (54.5) 
Thrombocytopenia 31/44 (70.5) 21/44 (47.7) 
Supportive treatment (during AZA administration), N (%)  
GCSF administration 16/44 (36.4) 
Erythropoietin administration 7/44 (15.9) 
Red blood cell transfusions 39/44 (88.6) 
Red blood cell transfusions (units/cycle), Median (range) 3 (0-7) 
Pooled random donor platelet transfusions 17 (38.6) 
Clinical adverse events, N (%)29/44 (65.9)
Neutropenic Infections 26/29 (89.7) 
Bloodstream Infection 9/26 (34.6) 
Lower respiratory infection 10/26 (38.5) 
Neutropenic Fever 8/26 (30.1) 
Septic shock 2/26 (7.7) 
Hemorrhagic events 2/29 (6.7) 
Cerebral hemorrhage (Grade 5) 1/2 (50.0) 
Epistaxis (Grade 3) 1/2 (50.0) 
Other (pyoderma gangrenosum) 1/29 (3.4) 
Laboratory incidents1, N (%) 44/44 (100) 
 All grades Grades 3/4 
Neutropenia 36/44 (81.8) 34/44 (77.3) 
Anemia 44/44 (100) 24/44 (54.5) 
Thrombocytopenia 31/44 (70.5) 21/44 (47.7) 
Supportive treatment (during AZA administration), N (%)  
GCSF administration 16/44 (36.4) 
Erythropoietin administration 7/44 (15.9) 
Red blood cell transfusions 39/44 (88.6) 
Red blood cell transfusions (units/cycle), Median (range) 3 (0-7) 
Pooled random donor platelet transfusions 17 (38.6) 

1According to the CTCAE Version 4.0

Disclosures

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.