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International Medical Scientific Journal        Issue-3 

10.5281/zenodo.5842838 

128 

  



Art of Medicine           Volume-1 

International Medical Scientific Journal        Issue-3 

10.5281/zenodo.5842838 

129 

 

 
 

 

 

Art of Medicine International Medical Scientific journal 

 

Founder and Publisher Pascual Izquierdo-Egea 

Published science may 2021 year. Issued Quarterly. 

Internet address: http://artofmedicineimsj.us 

E-mail: info@artofmedicineimsj.us 

11931 Barlow Pl Philadelphia, PA 19116, USA +1 (929) 266-0862 

 

 
  



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Comparative analysis of the results of therapy according to the protocols all-

bfm-95m and all-mb-2008 in Uzbekistan 

 

Ibragimova S.Z. 

Center for Professional Development of Medical Workers, Ministry of Health of the 

Republic of Uzbekistan, Tashkent, Uzbekistan 

 

Abstract. The results of treatment of 368 primary patients with ALL (aged 

from 1 to 18 years) were analyzed. Of these, 145 received treatment according to the 

ALL-BFM -95m protocol and 223 children according to the ALL-MB-2008 protocol 

in the children's department of the Republican Specialized Scientific and Practical 

Medical Center of Hematology. Clinical, morphological, immunological, molecular 

genetic research studies of bone marrow and statistical methods for processing the 

results. The results of therapy of 145 patients according to the ALL-BFM-95m 

protocol were analyzed. Overall survival (OS) was 48% ± 4% (67 patients). The 10-

year disease-free survival (EFS) was 48% ± 4% (67 patients). The cumulative 

recurrence risk (CIR) was 38% ± 4.1% (53 patients). There were 11.2% ± 2.6% of 

cases of deaths associated with therapy (TRD) - 16 patients. According to the results 

of therapy, 223 patients who received treatment according to the ALL_MB-2008 

protocol: overall survival (OS) was 75% ± 3% (162 patients). The 10-year relapse-

free survival (EFS) was 71% ± 3% (152 patients), the cumulative recurrence risk 

(CIR) was 16.4% ± 2.5% (36 patients). There were 8.8% ± 1.9% of cases of deaths 

associated with therapy (TRD) - 19 patients. In a comparative analysis of the results 

of treatment programs with different intensities of chemotherapy, 10-year relapse-

free survival (EFS) according to the All-BFM-95m protocol was 48% ± 4% versus 

71% ± 3% according to the ALL-MB-2008 protocol. The percentage of achieving 

remissions was higher in patients under the ALL-MB-2008 protocol, 95.1% (n = 213) 

compared to 90.3% under the All-BFM-95m protocol (n = 131, p = 0.0765). 

Thus, it is possible to reduce the intensity and toxicity of the chemotherapy 

performed without reducing the final results of treatment. At the same time, the high 

intensity of chemotherapy according to the All-BFM-95m protocol was the reason for 

the high induction mortality. 

Keywords: children, acute lymphoblastic leukemia, chemotherapy, risk 

groups, survival, relapse 

 

     Introduction. Acute lymphoblastic leukemia (ALL) occupies a leading 

place in the structure of oncohematological pathology in childhood and adolescence. 

It accounts for up to 20% of all malignant diseases (Fiel R.J. et al., 1988) and up to 

75% of all leukemias (Stiller C.A. et at., 1990) [1,2,9]. The high efficiency of ALL 

treatment in children is one of the most impressive achievements of modern 

medicine. The programs of chemotherapy, developed over the last period, ALL in 

children can achieve a cure in 80% of patients with ALL [3,4,6]. Currently, there are 

opportunities for organizing effective measures for early diagnosis, treatment and 



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prevention of complications [11,12]. In particular, the successful experience of 

introducing in Russia the original Moscow-Berlin protocol, created in cooperation 

with the Charite Clinic (Berlin, Germany), has shown the effectiveness of multicenter 

research technology in hematology/oncology to optimize the therapy of 

hematological malignancies in children [4,13]. 

Earlier in Uzbekistan, non-programmed treatment of ALL was carried out with 

a very low disease-free survival rate close to zero, then in 1999 it was started 

according to the ALL-BFM-95m protocol without immunophenotyping and 

molecular genetic analyzes, without stratification into risk groups. Since 2008, the 

implementation of the new ALL-MB-2008 protocol began, which involves risk-

adapted therapy using new diagnostic technologies [3,8]. Advances in ALL treatment 

have demonstrated the potential of modern high-dose chemotherapy, the role of 

concomitant therapy, and the important role of multicenter randomized clinical trials. 

In this ALL-MB-2008 protocol, stratification was carried out into 3 risk groups, 

which was carried out taking into account the size of the spleen, initial leukocytosis, 

the results of immunophenotyping and molecular genetic research [4, 2]. Isolation of 

such prognostic factors as the age and sex of patients, initial leukocytosis, lesions of 

the central nervous system and mediastinum, the immunological phenotype of the 

tumor substrate, served as a rationale for modifying therapy programs, reducing the 

toxic effects of therapy for patients with a good prognosis and, conversely, for 

intensifying treatment protocols for patients. high risk, which significantly increased 

their chances of survival [4,5,6]. Of all the known prognostic factors, only the factors 

associated with the ongoing therapy can be modified and improved as the treatment 

protocols are optimized [4,10,13]. 

Material and research methods. The results of treatment of 368 primary 

patients with ALL (aged from 1 to 18 years) were analyzed. Of these, 145 received 

treatment according to the ALL-BFM -95m protocol and 223 children according to 

the ALL-MB-2008 protocol in the children's department of the Republican 

Specialized Scientific and Practical Medical Center of Hematology. 

The analysis included 368 patients, including 226 boys (61.4%) and 142 girls 

(38.5%) aged 1 to 18 years (median age - 5.1 years).  

The number of boys (63.4% and 60.1%) and girls (36.6% and 39.9%), 

depending on the treatment protocol, is approximately the same (p = 0.5178). 

According to age groups, patients were distributed as follows: up to 10 years - 300 

(81.5%); from 10 to 18 years old - 68 (18.5%). The age composition of the patients of 

both groups is approximately the same: <10 years - 76.6% and 84.3%, >10 years - 

23.4% and 15.2%, respectively (p = 0.0476).  

There were 198 (53.8%) patients with initial leukocytosis in peripheral blood 

(PC) less than 10,000 / μl; more than 100,000 / μl - 54 (14.7%). Depending on the 

initial leukocytosis, the distribution of patients also does not differ: <10 thousand - 

51.7% and 55.2 (p = 0.5186), >10 thousand<30 thousand. - 17.7% and 9.5% (p = 

0.6837), >30 thousand<100 thousand. - 16.6% and 13% (p = 0.3436), >100 thousand 

- 15.9% and 13.9% (p = 0.6034).  



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The proportion of patients with an initial increase in the size of the spleen 

(more than 4 cm) was 38.3% (n = 141), did not depend on gender and was the same 

in different age groups. According to the size of the spleen, the distribution of 

patients is also the same: spleen <4 cm - 56.6% and 64.6%, spleen >4 cm - 43.4% 

and 35% (p = 0.1024).  

Initial CNS damage was registered in 5 (3.2% of patients), 2.8% and 0.4% in 

patients of two groups, respectively (p = 0.0614) (See Table 1.). 

Table 1. 

Initial characteristics of patients 

 

BFM-95 MB-2008 
p 

n % n % 

Total 145 100 223 100 
 

Sex 

Boys 92 63.4 134 60.1 
0.5178 

Girls 53 36.6 89 39.9 

Age 

<10 111 76.6 189 84.3 
0.0476 

>=10  34 23.4 34 15.2 

Leukocytosis 

<10 75 51.7 123 55.2 0.5186 

>=10 <30 23 15.9 39 17.5 0.6837 

>=30 <100 24 16.6 29 13 0.3436 

>=100  23 15.9 31 13.9 0.6034 

Spleen 

<4 82 56.6 145 64.6 
0.1024 

>=4 63 43.4 78 35 

Answer 8 day 

<1000 142 100.0 108 86.4 
<0.0001 

>=1000 0 0 17 13.6 

неизвестно 3 
 

98 
 

 
Answer 15 day 

<10 108 76.6 89 70.6 0.2689 

>=10 <30 25 17.7 12 9.5 0.0526 

>=30 7 5.0 25 19.8 0.0002 

неизвестно 5 
 

97 
 

 
CNS defeat 4 2.8 1 0.4 0.0614 

Immunophenotyping 

B-ALL 3 2.1 123 55.2 
 

non B-ALL 0 0 15 6.7 
 

Unknown 142 97.9 85 38.1 
 

Cytogenetics 

t(4;11) 0 0 0 0 
 

t(9;22) 0 0 4 1.8 
 

t(12;21) 0 0 8 3.6 
 

Unknow 145 100 154 69.1 
 

Risk group 

SRG 57 39.3 83 37.2 0.6864 



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ImRG 68 46.9 121 54.3 0.1672 

HRG 20 13.8 19 8.5 0.1083 

 

Research methods: clinical, morphological, immunological studies of bone 

marrow by flow cytofluorimetry in the Russian Children's Clinical Hospital 

(Moscow), molecular genetic research of bone marrow in the laboratory of biochip 

diagnostics of the Federal Scientific Clinical Center for Pediatric Hematology, 

Oncology and Immunology named after V.I. Dmitry Rogachev ”Ministry of Health 

and Social Development of Russia (Moscow) and statistical methods for processing 

the results. 

Results and discussion. 

The results of therapy of 145 patients according to the ALL-BFM-95m 

protocol were analyzed. Overall survival (OS) was 48% ± 4% (67 patients). The 10-

year disease-free survival (EFS) was 48% ± 4% (67 patients). The cumulative 

incidence of relapse (CIR) was 38% ± 4.1% (53 patients). There were 11.2% ± 2.6% 

of cases of deaths associated with therapy (TRD) - 16 patients. (See Figure 1). 

The results of therapy of 223 patients who received treatment according to the 

ALL-MB-2008 protocol were analyzed. Overall survival (OS) was 75% ± 3% (162 

patients). The 10-year disease-free survival (EFS) was 71% ± 3% (152 patients). The 

cumulative incidence of relapse (CIR) was 16.4% ± 2.5% (36 patients). There were 

8.8% ± 1.9% of cases of treatment-related death (TRD) - 19 patients. The results are 

presented in Figure 1 and Table 2. 

 
Fig. 1. Treatment results according to the protocols ALL-BFM-95m and ALL-

MB-2008 

 

Table 2. 



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Results of therapy by risk groups according to the ALL-BFM-95m protocol 

The distribution of patients by risk groups was SRG - 57 patients, 30 of them in 

CCR, EFS was 56%. 68 patients were assigned to the ImRg group, 30 in PPR, EFS 

was 46%. HRG was 20 patients, 7 in PR, EFS was 35%. There is also a high relapse 

rate in HRG of 40%. In the SRG group, 37.1% (20), in the ImRg group, 38% (25), 

the relapse rate is also high. A high percentage of relapses is possibly associated with 

an unknown immunophenotype and cytogenetics, the lack of the possibility of 

stratification into risk groups and, as a consequence, of adequate therapy, when all 

patients, regardless of the risk group, received the same therapy. (See Figure 2.) 

 



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Fig. 2. Results of treatment by risk groups according to the ALL-BFM-95m 

protocol 

It is noteworthy that the frequency of induction deaths is quite high and 

amounts to 6.9% for all patients, and 9.18% in the HRG group. Induction mortality 

rates did not differ in SRG and ImRG - 6.9%. Mortality in remission was 4.1%; it did 

not differ in the standard and intermediate risk groups. In 2.8% of patients were 

resistance (non-responder) to chemotherapy. There were no secondary tumors in the 

study group. In 53 patients (36.6%), the development of a relapse of ALL was 

recorded, while among SRG patients more than 70% of relapses developed 6 months 

after the end of therapy and later, then in ImRG and HRG patients, very early and 

early relapses prevailed. In general, and among individual risk groups, isolated bone 

marrow relapses prevailed. The incidence of relapses with CNS involvement was 

18.8% among all patients, 5.6% in SRG and 11.3% in ImRG. The incidence of 

combined BM+CNS relapses is higher in ImRG –3.7% (2); 5 patients lost to follow-

up 3.4% (LFU). Relapses with lesions of the testicles were registered in 2 (3.7%) 

patients, in 2 more patients with combined bone marrow and testicular. 

Results of therapy by risk groups according to the ALL-MB-2008 protocol 

The distribution of patients by risk groups was SRG - 83 patients, 68 of them in 

ССR, EFS was 83%. 121 patients were assigned to the ImRg group, 79 in PPR, EFS 

was 69%. HRG was 19 patients, 5 in ССR, EFS was 30%, it should be noted that due 

to the lack of the possibility of high-dose chemotherapy according to the ALL-MB-

2008 protocol and the possibility of performing allogeneic BMT, patients in this 

group received treatment at an intermediate risk group. There is also a high relapse 

rate in HRG of 42.5%. In the SRG group, 8.5% (7) relapses, in the ImRg group, 

18.2% (21) relapses were recorded. (See Figure 3) The high relapse rate in the 

intermediate risk group is possibly associated with a large number of patients with 

unknown immunophenotype and cytogenetics. 

 



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Figure 3. Results of treatment by risk groups according to the ALL-MB-

2008 protocol 

The incidence of induction deaths was 1.8% for all patients, 6.18% in the HRG 

group. Induction mortality rates did not differ in SRG and ImRG. Mortality in 

remission was 6.7%, did not differ in the groups of standard and intermediate risk and 

was about 5%. 

In 1 patient, the development of a secondary tumor was registered 15.2 months 

after the end of ALL therapy in the form of bladder cancer. 

In 36 patients (16.1%), the development of a relapse of ALL was recorded, 

while more than 50% of relapses were late among SRG patients, more early relapses 

were observed in ImRG and HRG patients. Isolated bone marrow relapses prevailed 

in all risk groups. There were 5 (13.8%) isolated CNS relapses among all patients, 

most of them were in ImRG, combined (BM+CNS) relapses were 2. There were only 

1 relapses with testicular lesions, and 1 Extramedullary relapse (EMR) in the form of 

unilateral damage to the cervical lymph node. 

Table 3. 

The number and location of relapses 

Localization of relapse All-BFM-

95 

ALL-MB-

2008 

P 

Bone marrow 37 (69,8%) 27 (75%) 0.2689 

CNS 10 (18,8%) 5 (13,8%) <0.0001 

Testicular 2 (3,7%) 1 (2,7%) 0.0002 

Combined (BM + CNS) 2 (3,7%) 2 (5,5%) 0.0614 

Combined (BM + testicular) 2 (3,7%) _  

Extramedullary relapse 

(EMR)  (cervical lymph node 

involvement) 

_ 1 (2,7%)  

Total 53 (36,6% 

of the total 

145) 

36 (16,1% of 

the total 223) 

<0.0001 

 

In a comparative analysis of the results of treatment programs with different 

intensities of chemotherapy, 10-year relapse-free survival (EFS) according to the All-

BFM-95m protocol was 48% ± 4% versus 71% ± 3% according to the ALL-MB-

2008 protocol. The percentage of achieving remissions was higher in patients in the 

ALL-MB-2008 protocol, 95.1% (n = 213) compared to 90.3% in the All-BFM-95m 

protocol (n = 131, p = 0.0765). It should be noted that induction mortality was high in 

patients of the first group (6.9%) compared with the second group (1.8%, p = 

0.0121). There is also a high TRD of 11.2% ± 2.6% versus 8.8% ± 1.9%. There were 

no significant differences in the number of non-responder patients. 

In a comparative analysis of the risk groups of the two protocols in the standard 

risk group (SRG), EFS in the All-BFM-95m group was 56% compared to EFS in the 

ALL-MB-2008 group of 83%, which is significantly higher. 



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In the All-BFM-95m group, the result of therapy in the intermediate risk group 

(ImRg) was 46% EFS, compared with a similar risk group in the ALL-MB-2008 

group of 69%, which is also significantly higher. In the HRG group under the All-

BFM-95m protocol, EFS was 35%, which is higher than under the ALL-MB-2008 

protocol, here EFS was 30%. But given the small number of patients, the comparison 

is unreliable. The relapse rate was significantly higher in SRG and ImRg risk groups 

when treated with the All-BFM-95m protocol. 

Conclusions. 

Thus, it is possible to reduce the intensity and toxicity of the chemotherapy 

performed without reducing the final results of treatment. At the same time, the high 

intensity of chemotherapy according to the All-BFM-95m protocol was the reason for 

the high induction lethality. The rate of death in remission in patients under the ALL-

MB-2008 protocol was somewhat high, 6.7% compared to 4.1% (p = 0.3010), but the 

difference was not statistically significant. About 90% of deaths are due to infectious 

complications. The number of relapses is significantly higher in the first group, 

36.6% (53) compared to 16.1% (36), and the difference is statistically significant (p 

<0.0001). Perhaps this is due to the fact that patients of the first group underwent the 

same chemotherapy regardless of the risk group, since it was not possible to carry out 

a full diagnosis (lack of immunophenotyping, cytogenetic studies) and stratification 

into risk groups, as well as non-compliance with the timing of treatment, in more than 

50% of patients with this In a group of patients, post-induction chemotherapy was 

performed with a delay of 10 days to 20 days, although the intensity of post-induction 

therapy was much higher. CCR in the first group of patients was 46.2% compared to 

67.9% in the second group, that is, significantly higher (p <0.0001). 

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