Acute Lymphoblastic Leukemia IC-BFM Research Articles

Influence of Minimal Residual Disease at Day 15 of Induction Therapy on Survival of Children with Acute Lymphoblastic Leukemia.

The aim of the study was to evaluate the impact of minimal residual disease (MRD) on day 15 of induction therapy (d15) on the treatment outcome in children with acute lymphoblastic leukemia (ALL). The study included 74 patients (1-18 years) with ALL, who were treated at the Pediatric Clinic of the University Clinical Center Banja Luka from January 2011 to May 2021. All patients were treated according to ALL IC-BFM 2009 protocol. MRD on bone marrow was assessed d15, using the multiparameter flow cytometry method (FCM). Of all, 59.46% of patients had MRD d15 0.1-10%, MRD<0.1% had 18.92% of patients, and 21.62% had MRD >10%. Patients with the lowest MRD had the highest 5-year overall survival (OS) and event-free survival (89.5% and 91% respectively) and the lowest cumulative risk for relapse or death (9.7% and 8.1%), in contrast to patients with MRD>10% in whom OS was 80.0%, and the risk of recurrence is 20%. Predicted MRD d15 was significantly associated with prednisone response assessed in the peripheral blood on day 8 (P<0.001) and statistically significantly positive correlation (r=0.498; P<0.001) was found. MRD measurement d15 has a great prognostic significance for patients in the standard and high risk groups, but not for patients in the intermediate risk group. The introduction of additional testing is necessary for better identification of patients with an increased risk of disease recurrence.

IL-6 and TGF-β as markers of air-blood barrier damage in children with acute lymphoblastic leukemia: сlinical and prognostic aspects

Background. Damage markers of blood-air barrier are important for studding pathological process in lungs in children with acute lymphoblastic leukemia (ALL).&#x0D; Purpose is to analyses pulmonary complications and to assess IL-6 and TGF-β levels in the exhaled breath condensate (EBC) in children with ALL and its prognostic value.&#x0D; Materials and Methods. 40 children with ALL aged 6–17 years were examined. 1st group included newly diagnosed ALL (n = 18). 2nd group involved ALL survivors who had completed course of ALL IC BFM 2009 protocols (n = 22). The control group consisted of 15 healthy children. The levels of IL-6 and TGF- β in the EBC were analyzed by ELISA.&#x0D; Results and discussion. Pulmonary complications presented in 82.5% of children with ALL during chemotherapy and in 15.8% of ALL survivors. IL-6 and TGF-β levels in EBC were significantly higher in both ALL groups than control: IL-6 p1-C = 0,000001; p2-C = 0,000000; TGF-β p1-C = 0.000014; p2-C = 0.009364. 1st group had higher levels of IL-6 and TGF-β in the EBC than 2nd group: IL-6 p1-2 = 0,000000; TGF-β p1-2 = 0.000141. There was a positive correlation between IL-6 and TGF-β levels (r = 0.681176, p = 0.000001). According to ROC analysis, IL-6 level in EBC collected during Protocol 1 &gt; 47.64 pg/ml can be prognostic for pulmonary complications during chemotherapy (AUC 0.875; Sensitivity 75.0%; Specificity 100,0%). Level of IL-6 &gt; 49.96 pg/ml can predict pneumonia during chemotherapy (AUC 0,883; Sensitivity 100.00%; Specificity 81.82%). IL-6 level after the total course of chemotherapy &gt; 23.64 pg/ml can predict pulmonary complications in ALL survivors (AUC 0.819; Sensitivity 75.00%; Specificity 81.82%). TGF-β level in EBC after the completion of chemotherapy &gt; 19.93 pg/ml can be prognostic for pulmonary complications in ALL survivors (AUC 0.896; Sensitivity 100.00%; Specificity 77.78%).&#x0D; Conclusions. IL-6 and TGF-β levels in EBC can be prognostic for pulmonary complications in children with ALL.

The role of minimal residual disease in therapy of pediatric acute lymphoblastic leukemia: a prospective cohort study

Background. During last 50 years there was a significant progress in understanding the nature of pediatric acute lymphoblastic leukemia (ALL). There were developed effective chemoradiotherapy regimens, new methods of diagnosis and emerged evaluation of treatment results. Determination of minimal residual disease (MRD) has become the most important factor in the patients stratification for risk-adapted treatment in the ALL IC-BFM 2009.&#x0D; Aim. To evaluate the survival rates of children with ALL according to the ALL IC-BFM 2009 protocol.&#x0D; Materials and methods. There were 136 people in the study of evaluating the effectiveness of therapy according to the ALL IC-BFM 2009 protocol: 69 boys and 67 girls (ratio 1.03:1). The median age is 4 years and 10 months. The observation period is from 26.01.2010 to 06.11.2022.&#x0D; Results. High survival rates of children with newly diagnosed ALL are achieved: overall survival (OS) is 91.2%, event-free (EFS) 82.4%, relapse-free (RFS) 88.6%. The best results are among patients of the standard risk group: OS, EFS and RFS reach 96.6%. In the intermediate group OS 96.2%, EFS 84.8% and RFS 88.3%. Worse results of survival are in the high risk group: OS 76.9%, EFS 65.4% and RFS 80.7%. Outcome analysis depending on the linear reveals a statistically insignificant difference in survival rates (for B-ALL OS 92.4%, EFS 83.1% and RFS 89.5%, for T-ALL OS 83.3%, EFS 77.8% and RFS 83.3%). It determines the tendency of improving the prognosis of pediatric T-ALL by optimizing the stratification of patients based on the indicators of MRD and the best direction of protocol.&#x0D; Conclusion. Results of survival rates of patients with ALL confirm high effectiveness of treatment according to the ALL IC-BFM 2009 protocol. MRD level on day 15 makes it possible to stratify patients and choose the optimal risk-adapted therapy.

Pediatric Acute Lymphoblastic Leukemia: Russian Experience with the ALL-IC BFM 2002 Protocol

Background: Treatment protocols for pediatric acute lymphoblastic leukemia (ALL) developed by the BFM (Berlin-FrankfurtMunster) group are among the most effective in the world. The longstanding overall survival rate of children with ALL is more than 90%. The highly successful treatment results obtained for ALL are the reason that the ALL-IC BFM 2002 protocol is widely used in Russia. Aim: This study presents the results of the Russian multicenter study for pediatric ALL treatment by the ALL ICBFM 2002 rotocol. Materials and Methods: In total, 433 patients with primary ALL from 10 Russian pediatric hematology/oncology clinics were included in retrospective and prospective studies from 01.11.2003 to 12.10.2021. The ages of the patients ranged from 3 months to 21 years. All patients were treated according to the ALL IC-BFM 2002 protocol. The overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) were assessed on 11.12.2021. Results: An overwhelming majority of patients, 97.9% (n=424), achieved clinical and laboratory remission by 33 days of treatment based on the ALL IC-BFM 2002 protocol. The 10-year OS was 91.8+/-1.5%, the RFS was 87.4+/-1.8%, and the EFS was 84.1+/-1.9%. The results of the 10-year OS in the standard-risk and intermediate-risk groups were 92+/-1.7%, and 93.1+/- 3.0%, respectively, and the percentage of relapse in the high-risk group was 71.1+/-11.1%. Conclusion: The ALL-IC BFM 2002 protocol for pediatric ALL could be performed in Russian federal and regional clinics. The treatment results for ALL using the ALL-IC BFM 2002 protocol are dramatic and comparable to those of leading clinics in Europe and the United States. To improve the survival rate in high-risk groups of patients, it is necessary to use additional risk-stratifying factors such as minimal residual disease (MRD).

Minimal residual disease in B-precursor acute lymphoblastic leukemia: Clinical significance on post-induction treatment

Minimal residual disease (MRD) assessment in patients with acute lymphoblastic leukemia (ALL) became an integral part of total evaluation of chemotherapy efficacy. No doubt, that it is necessary to evaluate MRD at remission induction and before allogenic stem cell transplantation, but MRD prognostic role at post-induction treatment is on-study.Aim. To evaluate a prognostic significance of MRD at post-induction treatment in pediatric patients with ALL.Materials and methods. From October 2010 to September 2022, there were 142 pediatric patients with primary diagnosed B-precursor ALL enrolled the study. All the patients were treated by ALL–IC BFM 2009 protocol.Results. 6-year overall survival (OS) for patients with MRD-positive status at post-induction treatment (78th day of therapy) was 90.8 ± 4.0 %, with MRD-negative – 91,1 ± 3.9 % (р = 0,8). Relapse-free survival (RFS) for MRD-positive – 67.4 ± 11.6 %, MRD-negative – 88.9 ± 4.3 % (р = 0,03). Event-free survival for MRD-positive – 67.4 ± 11.6 %, MRD-negative – 87,5 ± 4.5 % (р = 0,06).Conclusion. MRD level at induction remission treatment is an important risk-stratified factor in pediatric patients with ALL, but prognostic significance of MRD at post-induction therapy is under investigation. Presented our data showed increased relapse incidence on 21.5 % in patients with MRDpositive status at 78th day of therapy. OS was the same and not depended on post-induction MRD-level.

Comparison of Dexamethasone Versus Prednisolone Prephase in Induction Therapy of Pediatric Acute Lymphoblastic Leukemia: A Single-Center, Randomized Controlled Study from India

Background: Acute lymphoblastic leukemia (ALL) is the commonest cancer in children. Despite advances in treatment, approximately 20% of pediatric ALL patients still relapse. Although the use of dexamethasone in induction regimen has been reported to significantly decrease CNS relapse risk & improve event-free survival (EFS) compared to prednisolone, there are concerns of significant toxicities like infection & osteonecrosis with dexamethasone. Objectives: The aim of this single-center randomized study was to compare the efficacy and safety of dexamethasone prephase versus prednisolone prephase during the initial seven days (days 1 - 7) of induction chemotherapy in newly diagnosed pediatric ALL patients treated with ALL IC-BFM 2009 protocol,in terms of day 8 steroid response, day 15 bone marrow minimal residual disease (MRD) response, and day 33 morphological complete remission (CR) rates. Methods: The study enrolled total 62 newly diagnosed pediatric ALL patients (age > 1 year & ≤ 18 years) between June 2019 and April 2021, after obtaining informed consent and with institutional ethics committee approval. Patients with lymphoblastic lymphoma (LBL) and infantile ALL (age < 1 year) were excluded. Patients who were randomized to dexamethasone prephase group received intravenous dexamethasone 10 mg/m2/day on days 1-7 of induction,& those in prednisolone prephase group received prednisolone 60 mg/m2/day p.o. in three divided doses on days 1-7 of induction therapy .All the patients subsequently received prednisolone 60 mg/m2/day p.o. in three divided doses on days 8 - 28 of induction, followed by prednisolone taper over next 7 days. Induction regimen of ALL IC-BFM 2009 protocol was given. The cut-off values for day 15 BM Flow-MRD were <0.1%, 0.1-10%, and >10% as per ALL IC-BFM 2009 protocol. Morphological complete remission on day 33 was defined as bone marrow blasts < 5% of total nucleated cells, with normocellular or mildly hypocellular marrow. Steroid-related toxicities in the two treatment groups were compared as per NCI-CTCAE version 5. Results: Out of total 62 patients, 33 patients (53%) received dexamethasone prephase and 29 patients (47%) received prednisolone prephase. Forty-six patients (75%) had B-cell ALL, and 25% had T-cell ALL. The distribution of patients in standard-risk, intermediate-risk & high-risk groups as per ALL IC-BFM 2009 protocol risk stratification were 18%, 34% and 48% respectively. Twenty-nine out of 33 patients (88%) in dexamethasone prephase group achieved good steroid response on day 8 (peripheral blood absolute blast count < 1000/µl) compared to 17/29 patients (59%) in prednisolone prephase group [p = 0.018]. Day 15 bone marrow MRD assessment by flowcytometry was available in 57 patients (31/33 in dexamethasone prephase group & 26/29 in prednisolone prephase group). Nineteen out of 31 patients (61%) in dexamethasone prephase group achieved day 15 MRD < 0.1% compared to 6/26 patients (23%) in prednisolone prephase group [p = 0.02]. Twenty-eight out of 30 patients (93%) in dexamethasone group achieved morphological CR on day 33 of induction compared to 18/24 patients (75%) in prednisolone prephase group [p = 0.135]. Day 33 bone marrow Flow-MRD < 0.1% in the dexamethasone & prednisolone prephase groups were 82% and 50% respectively [p = 0.12]. At the time of analysis, 3/30 patients (10%) in dexamethasone group who achieved CR has disease relapse, compared to 8/24 patients (33%) in prednisolone prephase group [p = 0.04]. The event-free survival (EFS) at the end of study (18 months) was found to be significantly higher in the dexamethasone prephase group compared to prednisolone prephase group (p = 0.002). The incidence of steroid-related toxicities of any grade was similar in the two treatment groups. Conclusion: In the present study, the replacement of prednisolone with dexamethasone for a relatively shorter duration in the 7-day steroid prephase of ALL IC-BFM 2009 induction regimen was associated with significantly improved day 8 steroid response, day 15 bone marrow Flow-MRD response, day 33 morphological CR rates, and EFS at 18 months, without significant increase in steroid-related toxicity in induction. To our knowledge, this is the only study to compare dexamethasone versus prednisolone prephase in pediatric ALL induction, in the context of ALL IC-BFM 2009 regimen. Long-term follow up and enrollment of larger number of patients is planned. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pediatric acute lymphoblastic leukemia: multicenter study of the treatment by the protocol ALL IC-BFM 2002

Background. Recovery of children with acute lymphoblastic leukemia (ALL) was one of the most significant achievements of clinical oncohematology of XX century. Success in the treatment of ALL became possible due to comprehensive (clinical, morphoimmunological, cytogenetic) diagnostics and the development of differentiated, risk-adapted treatment protocols. The German group BFM (Berlin–Frankfurt–Munster) became a pioneer in creating effective treatment programs for children with ALL. Its new principles and approaches in treatment allow the vast majority of patients to be cured.The aim of the study – presentation of the treatment results of children with ALL based on the ALL IC-BFM 2002 protocol as part of a multicenter long standing study.Materials and methods. There were 592 patients with a newly diagnosed ALL in the study . The average age of patients was 10.5 years (from 4 months to 21 years). Treatment was carried out according to the ALL IC-BFM 2002 protocol in 11 clinics from 01.11.2003 to 16.05.2022. The overall (OS), relapse-free (RFS) and event-free (EFS) survivals of patients were estimated on 01.07.2022.Results. Complete clinical and hematological remission was achieved by the 33 day of therapy in 582 (98.3 %) cases. 10-year OS was 90.4 ± 1.5 %, RFS – 83.9 ± 1.9 % EFS – 82.4 ± 1.9 %. The analysis of survival of ALL patients in prognostic risk groups showed that 10-year OS in the standard risk group was 92.8 ± 1.7 %, RFS – 86 ± 2.2 % and EFS – 84.3 ± 2.2 %. Among the patients of the intermediate risk group the OS, RFS and EFS were 94.6 ± 2.6 %, 82.2 ± 5 % and 81.7 ± 5 %, respectively. The prognosis of ALL patients from the high-risk group turned out to be the least favorable: OS was 69.5 ± 8.7 %, RFS – 62 ± 9.4 % and EFS – 60.3 ± 9.3 %.Conclusion. Based on the results of a multicenter study the ALL IC-BFM 2002 protocol showed high efficiency with the possibility of achieving a 10-year OS of 90.4 ± 1.5 %. This protocol turned out to be reproducible both in federal and regional clinics with high rates of long-term patients survival. This fact allows including it in the clinical recommendations of the Ministry of Health of Russia.

Chemotherapy as a risk factor for caries and gingivitis in children with acute lymphoblastic leukemia: A retrospective cohort study.

Dental and oral anomalies are among the most common long-term side effects of childhood cancer therapy. To evaluate chemotherapy as a risk factor for caries lesions and gingivitis in children with acute lymphoblastic leukemia (ALL) treated with the ALL IC-BFM 2009 chemotherapy protocol. A retrospective cohort study was designed. Clinical records of 23 paediatric patients with ALL exposed to chemotherapy in the Regional Hospital in Valdivia, Chile, and 46 unexposed patients assessed every 3months for 24months were analyzed. The data on gender, age, index of the number of decayed, missing, or filled teeth, and the presence of gingivitis were recorded (Mann-Whitney U test and logistic regression analysis, p≤.05). A significantly greater frequency of gingivitis (69.57%; p<.002) and a mean of new caries lesions were observed in children treated with chemotherapy than in the unexposed children (p<.01). The chemotherapy protocol presented a relative risk of 2.15 (95% CI=1.22 - 2.66; p=.01) for new caries lesions and 2.29 (95% CI=1.76 - 3.82; p=.002) for gingivitis. The ALL IC-BFM 2009 chemotherapy protocol in patients with ALL is a risk factor for new caries lesions and gingivitis.

Methotrexate(MTX) Induced Leukoencephalopathy(LE) and Relation of Vitamin B12, Folate and / or Homocysteine Levels with MTX Toxicity: A Prospective Study

▪Background: MTX-induced neurotoxicity is often associated with leukoencephalopathy, and the diagnostic radiological feature in magnetic resonance imaging (MRI) is white matter hyper intensities. The clinical significance of these white matter changes is unknown. The risk factors of MTX-induced acute leukoencephalopathy are not well established. Few authors have suggested increased homocysteine or alteration of Central Nervous System (CNS) folate, vitamin b12 homeostasis may be associated with CNS toxicity. It is a usual clinical practice to withhold methotrexate during further duration of chemotherapy after an episode of leukoencephalopathy but the risk of neurotoxicity must be weighed against the risk of relapse of leukemia. Moreover, there is limited data on continued treatment with High-dose methotrexate (HD-MTX) or Intrathecal Methotrexate (IT-MTX) or Oral-MTX in patients who developed leukoencephalopathy.Objective: The study aims to 1) identify the risk and prevalence of leukoencephalopathy in patients of Acute Lymphoblastic Leukemia (ALL) receiving intrathecal or high dose or oral methotrexate therapy through sequential MRI Brain study. 2) Safety of re-administration of methotrexate in patients with documented toxic leukoencephalopathy 3) The relationship of serum homocysteine, vitamin b12 and folate levels with methotrexate induced leukoencephalopathyMethods: Our study enrolled 34 newly diagnosed pediatric ALL / Lymphoblastic Lymphoma (LBL) patients (age ≤18 years) between June 2019 & June 2020. Induction chemotherapy was initiated as per modified ALL IC BFM 2002 protocol after obtaining informed consent. Apart from the Hematological investigations, Bone Marrow Aspiration and Biopsy, Flow Cytometry/Immunohistochemistry (IHC), Cytogenetics, Molecular study were done. All the patients underwent MRI Brain and Serum homocysteine, Vitamin B12, Folate level measurement (sequentially as per protocol at 4 different time points). 1st time point - AT DIAGNOSIS, i.e. before starting methotrexate, 2nd time point - POST CONSOLIDATION, 3rd time point - POST EXTRACOMPARTMENT THERAPY, 4th time point - IN MAINTENANCE, thus analyzing leukoencephalopathy secondary to different modes of administration of methotrexate therapy. At all-time points serum folate, vitamin b12 or homocysteine level were done before administering methotrexate and any association with development of leukoencephalopathy was analyzed.Results: We identified Leukoencephalopathy secondary to methotrexate in 6.03% (7/116) on MRI brain in 5 of 33 (15.15%) patients of which 1 (3.03%) had symptomatic LE and 4 (12.12%) were clinically asymptomatic. All our LE patients were in the age group more than or equal to 10 years. We found no increase in the incidence of leukoencephalopathy secondary to methotrexate: leucovorin ratio, also there was no difference in the incidence with respect to mode of administration of MTX (IT/HD/ORAL), even there was no increase in incidence after 4 courses of high dose methotrexate. MRI at baseline was not a predictor of development of leukoencephalopathy. 3 out of 5 patients with LE had abnormal b12/folate/homocysteine with corresponding abnormal MRI Brain at pre-specified time point. Also 4 patients with abnormal b12/folate/homocysteine levels had intractable cytopenias while on chemotherapy and more after HD MTX therapy which got corrected after supplementation with vitamin b12 and folic acid.Conclusion: MTX-induced clinical leukoencephalopathy is transient, and most patients can be re-challenged with subsequent MTX without recurrence of acute or subacute symptoms. MRI at baseline was not a predictor of development of leukoencephalopathy. More multi institutional prospective studies of large number of patients are needed to study the incidence of MTX-induced leukoencephalopathy and its relation with folic acid, vitamin b12 and homocysteine level. DisclosuresNo relevant conflicts of interest to declare.

Treatment of acute lymphoblastic leukemia in children by ALL IC-BFM 2002 protocol: results of multicenter retrospective study

By the whole history of pediatric acute lymphoblastic leukemia (ALL) treatment protocols development, one of the World ideologist of original science-based therapeutic approaches was German group BFM (Berlin–Frankfurt–Münster). It is not surprisingly that modern ALL treatment protocols, developed by BFM group are high-effective and use in many countries. Understanding the probability of recovery of overwhelming ALL patients majority treated by ALL IC-BFM 2002 protocol, the Scientific-Practical Board of Ministry of Health of Russia in 2020 adopted a protocol as clinical recommendation for pediatric ALL treatment (ID:529).It the current issue BFM ALL treatment protocols evolution is presented and first Russian multicenter experience in pediatric ALL treatment by ALL IC-BFM 2002 protocol. It was 408 pediatric and adolescents patients with primary ALL included the study. All of them were treated by ALL IC-BFM 2002 protocol from 01.11.2003 to 12.05.2021. Survival rate was estimated on 01.06.2021.ALL IC-BFM 2002 demonstrated a high efficiency in multicenter retrospective study. 15-year event-free survival was 83.7 ± 2.1 %, relapsefree survival – 88 ± 1.8 % and overall survival – 93.4 ± 1.4 %. So, ALL IC-BFM 2002 protocol could be realized in Russian clinics and give results similar to world’s leading medical centers.

Acute non-hematological toxicity of intensive chemotherapy of acute lymphoblastic leukemia in children

AbstractIntroductionLeukemia belong to 31% of all childhood malignancies. Acute lymphoblastic leukemia (ALL) is the most frequent type of pediatric leukemia accounting for 80–85% of all cases. Progress in diagnostics and therapy of leukemia is dependent on international cooperation. The objective of the study was the analysis of non-hematological toxicity during intensive chemotherapy according to two consecutive intercontinental protocols.Patients and methodsA total number of 210 children diagnosed for ALL who were treated in single center between 2002 and 2018 were divided in two groups defined by therapeutic protocol: ALL IC-BFM 2002 (group 1) and ALL IC-BFM 2009 (group 2). Data were entered prospectively from 2002 into international ALL IC-BFM 2002 and ALL IC-BFM 2009 registry. Non-hematological toxicity was analyzed according to the criteria followed in protocols, compatible with CTCAE criteria.ResultsThe most frequent toxicities included hepatic toxicity with transaminitis and hyperbilirubinemia, infections, oral mucositis and gut toxicity with vomiting, and/or diarrhea. Non-hematological toxicity episodes calculated as a ratio per patient were comparably often observed in both the groups; however, the distribution was different. There were more grade III and less grade II toxicities. This was mainly related to significant increase in the rates of infections and transaminitis. However, there was a significant decrease in vomiting and central and peripheral neurotoxicity.ConclusionsIntensive treatment of ALL is burdened with frequent severe toxic and infectious complications. Further progress in therapy of pediatric ALL is dependent on sophisticated supportive therapy and very well experienced and knowledgeable therapeutic team.

Clinical Characteristics and Treatment Results of Childhood Acute Lymphoblastic Leukemia in North Macedonia.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. This study was designed to determine the clinical, biological features and outcomes among children with ALL treated at the only pediatric hematology-oncology center in North Macedonia. Seventy four consecutive children age 1 to 14 years, diagnosed with ALL between January 1, 2010 and October 31, 2017 and treated according to ALL IC BFM 2002 protocol were retrospectively evaluated. The median age at diagnosis was 5 years and males were predominant (60.8%). Precursor B-cell ALL was diagnosed in 81.1% of patients, while 18.9% had T cell ALL. CNS involvement at the time of diagnoses was present in 6.8% of patients. Complete remission was achieved in 93.2% of patients. The induction death rate was 5.4%. The rate of death during first complete remission was 4.1%. Relapse occurred in 13.5% of patients. After a median observation time of 44 months, the 5-year overall survival (OS) and event-free survival (EFS) rates (± standard error) were 79.4% ± 5.2% and 74% ± 5.7%, respectively. The 5-year EFS rate for patients categorized as standard risk by NCI criteria was significantly higher than for high risk patients (83.3% versus 46.7%; P<0.001). Patients with precursor B-cell ALL and negative minimal residual disease (MRD) status at the end of induction had the best prognoses. Our study demonstrated that the treatment results of childhood ALL in North Macedonia are comparable to those obtained in the ALL IC BFM 2002 trial.

Prospects for evaluation of the minimal residual disease in the post-induction period in pediatric B-precursor acute lymphoblastic leukemia

Relevance.Currently, the assessment of the level of minimal residual disease (MRD) is the standard in evaluating the effectiveness of therapy in acute lymphoblastic leukemia (ALL) in adults and children. Although, the necessity to study MRD at the induction therapy is not in doubt, the prognostic value of MRD in the period after induction is the subject for scientific discussion. Several studies suggest that MRD-positive status after induction chemotherapy associated with poor prognosis, and the reappearance of significant level MRD during follow-up allows impending relapse to be identified and to begin appropriate therapy in low leukemic cells level.Aim– to determine the prognostic value of post-induction MRD on overall (OS), relapse-free (RFS), and event-free (EFS) survival in children with B-precursor ALL who received program treatment at the N.N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of Russia.Materials and methods.The study included 73 pediatric patients with initial B-precursor ALL. The median age of the patients was 5.2 years (from 1 to 16 years). The treatment was according to the ALL IC-BFM 2009 protocol. MRD detected on day 15 and 33 of induction therapy, and day 78 of consolidation beginning. MRD level was determined by flow cytometry method.Results.EFS and RFS were the same for patients with MRD-positive status on 78 day of treatment 76.8 ± 12.3 % and 96.2 ± 2.6 % for MRDnegative (p = 0.06). Detailed assessment of MRD revealed a cohort of high-risk patients with MRD-negative status on 78 day of therapy with 100 % OS (observation time – 6 years).Conclusion.In all risk groups, patients with negative MRD status showed a better survival result, which indicates the possibility of additional stratification by risk groups not only at the induction, but also during a consolidating treatment protocol.

First-line treatment failure in childhood acute lymphoblastic leukemia: The polish pediatric leukemia and lymphoma study group experience.

The aim of this study was to evaluate the risk factors of relapse and treatment-related deaths in acute lymphoblastic leukemia (ALL) in children residing in Poland.A total of 1872 patients with newly diagnosed ALL, treated according to the ALL IC-BFM 2002 protocol in 14 Polish pediatric hematology centers from 2002 to 2012 were included in the study. Three-hundred eighty-four patients experienced treatment failure. The last follow-up was 31 December, 2016.Univariate analysis identified factors in each risk group that were significantly different between children whose treatment failed and those who remained in the first remission. Multivariate analysis demonstrated that only the age of 10 years or over at primary diagnosis in the high-risk group was an adverse prognostic factor. To facilitate the analysis, patients were divided into three groups: relapsed children who survived; relapsed children who died; children without relapse who died due to toxicity.Our analysis showed that age older than 10 years is a particular risk factor for the failure of first-line of treatment, both in terms of relapse and treatment-related mortality.

Circulating microRNAs as minimal residual disease biomarkers in childhood acute lymphoblastic leukemia

BackgroundTreatment stratification based on bone marrow minimal residual disease (MRD) at set time points has resulted in considerably improved survival in pediatric acute lymphoblastic leukemia (ALL). Treatment response is assessed using bone marrow samples. MicroRNAs (miRs) easily traffic among fluid spaces and are more stable than most other RNA classes. We examined the role of circulating miRs as putative less invasive MRD biomarkers.MethodsIn an exploratory experiment, expression of 46 preselected miRs was studied in platelet-free blood plasma samples of 15 de novo, 5 relapsed ALL patients and 10 controls by Custom TaqMan Array Advanced MicroRNA Card. Based on their high expression in ALL compared to controls, and on the reduction observed along the induction therapy, four miRs were selected for further analyses: miR-128-3p, -181a-5p, -181b-5p and 222-3p. Their expression was measured by qPCR at 4 time points in 27 de novo ALL patients treated in the ALL IC-BFM 2009 study.ResultsThe expression of all 4 miRs significantly decreased over the first week of therapy (miR-128-3p: log2 fold change − 2.86; adjusted p 3.6 × 10−7; miR-181b-5p: log2 fold change − 1.75; adjusted p 1.48 × 10−2; miR-181a-5p: log2 fold change -1.33; adjusted p 3.12 × 10−2; miR-222-3p: log2 fold change − 1.25; adjusted p 1.66 × 10−2). However, no significant further reduction in miR expression was found after the 8th day of therapy. Measured drop in expression of 2 miRs at day 8 strongly correlated with day 15 bone marrow flow cytometry MRD results (miR-128-3p: Pearson’s r = 0.88, adjusted p = 2.71 × 10−4; miR-222-3p: r = 0.81, adjusted p = 2.99 × 10−3).ConclusionIn conclusion, these circulating miRs might act as biomarkers of residual leukemia. MiR-128-3p and miR-222-3p in blood predict day 15 flow cytometry MRD results 7 days earlier. Although, their sensitivity falls behind that of bone marrow flow cytometry MRD at day 15.

Encouraging Results with ALL IC-BFM 2009 Protocol Therapy in Pediatric Acute Lymphoblastic Leukemia/Lymphoma in Resource-Limited Setting: A Single-Center Study from India

Background: Acute lymphoblastic leukemia (ALL) is the commonest cancer in children. The survival rates in pediatric ALL have improved to 80-90% in high-income countries, where the goal of current risk-adapted treatment protocols is to minimize treatment-related mortality. In contrast, cure/survival rates are still lower in low-income countries, due to combined effect of disease-related factors, high incidence of treatment abandonment, higher rates of relapse, &amp; higher treatment-related mortality. The Berlin-Frankfurt-Münster (BFM) protocol versions are commonly used for treatment of pediatric ALL in many centers. There is no published data on treatment outcomes with ALL IC-BFM 2009 protocol in pediatric ALL in India. Objective: The study aims to evaluate the treatment outcomes in Indian pediatric ALL/LBL patients treated with ALL IC-BFM 2009 protocol under severe resource-limited settings, in terms of morphological complete remission (CR), minimal residual disease (MRD) status, and disease-free survival. Methods: Our study enrolled 25 newly diagnosed pediatric ALL/LBL patients (age ≤18 years) between February 2018 &amp; June 2019. Induction chemotherapy was initiated as per ALL IC-BFM 2009 protocol after obtaining informed consent. Risk stratification was done as per protocol into standard risk (SR), intermediate risk (IR), and high risk (HR) groups, based on age, baseline leukocyte count, cytogenetics &amp; molecular study findings, day 8 steroid response (peripheral blood absolute blast count), bone marrow MRD by flowcytometry on day 15, and bone marrow morphological response on days 15 &amp; 33 of induction phase. Additional imaging was done to assess response in LBL patients. Central nervous system (CNS)-directed therapy with intrathecal chemotherapy was administered as per protocol. Post-induction therapy consisted of an augmented early intensification phase, risk-adapted consolidation therapy phase, a delayed intensification (reinduction) phase, &amp; maintenance phase. Therapeutic cranial radiation (18 Gy) was administered only to patients with documented CNS leukemia. Results: Of the total 25 patients, 17 had B-ALL, six had T-ALL &amp; two had T-LBL. Median age of patients was 9 years (2-18 years), with 11 boys &amp; 14 girls. All the patients had BCR-ABL negative disease; three patients had t(12;21)(p13;q22)/ETV6-RUNX1. Seven patients (28%) had hyperleukocytosis (leukocyte count &gt;1,00,000/µL) and two patients had CNS leukemia at presentation. Nine out of the 25 patients (36%) were in high risk group as per criteria. Eight patients (32%) had poor steroid response on day 8 of induction (PB blasts ≥ 1000/µL). Six patients had M3 marrow on day 15 (&gt;25% blasts in marrow). Day 15 bone marrow MRD was &lt;0.1% in 13 patients (52%), &gt;0.1% in 7 patients (28%) and could not be done in 5 patients (including the two T-LBL patients). Twenty-three out of 25 patients (92%) achieved morphological CR (marrow blasts &lt;5%) on day 33. There were two deaths in induction; both patients were not in CR as per day 33 bone marrow morphology criteria. One B-ALL patient in HR group died of early medullary relapse. The remaining 22 patients are in CR &amp; doing well on follow up, and four of them have started maintenance phase therapy. The results are summarized in Table 1. Conclusion: Our preliminary results with ALL IC-BFM 2009 treatment protocol in Indian pediatric ALL/LBL patients are encouraging, with 92% complete remission rate, 88% disease-free survival and manageable treatment-related toxicity in spite of severe resource constraints. Long-term follow up &amp; enrollment of higher number of patients is planned. Disclosures No relevant conflicts of interest to declare.

Clinical Significance of Minimal Residual Disease at the End of Remission Induction Therapy in Childhood Acute Lymphoblastic Leukemia.

BACKGROUND:Detection of minimal residual disease (MRD) in the early phase of therapy is the most powerful predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL).AIM:We aimed to determine the significance of MRD at the end of remission induction therapy in the prediction of treatment outcome in children with ALL.METHODS:Sixty-four consecutive patients aged 1-14 years with newly diagnosed ALL were enrolled in this study from January 2010 to October 2017. All patients were treated according to the ALL IC BFM 2002 protocol. MRD was detected at the end of remission induction therapy (day 33) by multiparameter 6-colour flow cytometry performed on bone marrow specimens with a sensitivity of 0.01%.RESULTS:Overall, 42.2% of patients had detectable MRD on day 33 of therapy. MRD measurements were not significantly related to presenting characteristics but were associated with a poorer blast clearance on day 8 and 15 of remission induction therapy. Patients with negative MRD status on day 33 had a 5-year event-free survival of 94.6% compared with 76.1% for those with positive MRD status (P = 0.044).CONCLUSION:MRD levels at the end of remission induction therapy measured by multiparameter flow cytometry have clinical significance in childhood ALL. High levels of MRD are strongly related to poor treatment outcome.

Infectious profile in children with ALL during chemotherapy: A report of study group for infections

IntroductionThe treatment-related mortality in currently published studies of acute lymphoblastic leukemia (ALL) in children is 2–4%, mainly due to infections. The aim of the study was to analyse the incidence, epidemiology, profile of infection and the death rate in children with ALL. Patients and methodsThe retrospective analysis included 1363 patients, aged 1–18 years, with newly diagnosed ALL, who were treated in 17 pediatric hematology centers between 2012 and 2017 in Poland. The patients received therapy according to the ALL IC-BFM 2002 and 2009 (International Berlin-Frankfurt-Munster Study Group) protocols. ResultsIn our study, 726 out of 1363 (53.2%) children were reported to have a microbiologically documented bacterial infection during chemotherapy. 1511 episodes of these infection were diagnosed. A total number of 251/1363 (18.4%) children experienced a viral infection. 304 episodes were documented by PCR test (polymerase chain reaction). A fungal infection was reported in 278 (20.4%) children, including 10.1% of probable, 6.0% of proven, 83% of possible diagnosis. A higher frequency of fungal infection was noted in the recent years. In our material, the rate of death was 2.4%, mainly due to fungal infection. ConclusionsOur results present the epidemiology of infectious disease in the Polish ALL patient population. The most frequent were bacterial infections, followed by fungal and viral ones. Similar to the previously published data, the mortality rate in our material was 2.4%.

Diagnosis of Acute Lymphoblastic Leukemia Originating From T-Lineage Precursors and Approaches to Minimal Residual Disease Monitoring

Background. Minimal residual disease (MRD) is an independent prognostic factor in acute lymphoblastic leukemia (ALL) in children. The immunological assessment of MRD cell count is based on aberrant immunophenotype of tumor lymphoblasts. However, in the case of ALL originating from T-lineage precursor cells (T-ALL) no clear aberrancy criteria have been defined, yet. Flow-cytometric MRD assessment in T-ALL can be based on characteristics of normal T-cell ontogenesis, i.e. the absence of normal T-lineage precursor cells (T-LP) in bone marrow. Aim. To assess the feasibility of immunological method of flow cytometry for MRD detection based on T-LP immunophenotype on Days 15 and 33 of treatment of T-ALL children. Materials &amp; Methods. The analysis included the data on primary immunophenotype and MRD assessment on Days 15 and 33 of treatment of 31 T-ALL patients in the age of 2-17 years. In the majority of cases (61.3 %) the cortical/ thymic immuno-subvariant of ALL was detected, in the rest of cases (38.7 %) it was the pre-T-cell one. Diagnosis was based on cumulative results of morphocytochemical and immunological bone marrow analyses. Assessing the MRD state the morphological and immunological analyses of bone marrow aspirate were carried out in parallel with one and the same tube. All patients enrolled in the trial were treated at Scientific Research Institute of Pediatric Oncology and Hematology of NN Blokhin National Medical Cancer Research Center according to the ALL IC-BFM 2009 protocol. Results. Our study demonstrated that at all therapy stages MRD can be assessed by the unified immunological method based on detecting cyCD3&lt;sup&gt;+&lt;/sup&gt;CD7&lt;sup&gt;+/++&lt;/sup&gt;smCD3&lt;sup&gt;-&lt;/sup&gt; (T-LP) immunophenotype cells. It is important to ensure that the correct clones of monoclonal antibodies are used for detecting CD3 cytoplasmic and membrane molecules (UCHT1 and SK7, respectively). Standard risk group included no patients. The majority of patients (76.2 %) treated according to ALL IC-BFM 2009 protocol were assigned to medium risk group on Day 15 of treatment. By Day 33 a quarter of them (25 %) was included into high risk group. Conclusion. The capabilities of multicolor flow cytometry allow for the most complete characterization of primary immu-nophenotype of tumor T-cell lymphoblasts for further search of leukemia-associated immunophenotypes. Specific ontogenesis features of normal T-cells enable unification of immunological approaches to MRD assessment at all stages of T-ALL therapy.

Antithrombin III as the Indicator of L-Asparaginase Activity in Children Treated for Acute Lymphoblastic Leukemia.

L-asparaginase (ASP) is widely used in the treatment of acute lymphoblastic leukemia (ALL) in children. Monitoring its activity is necessary because of the risk of drug inactivation as the result of an immune reaction. Besides allergic reactions, another frequent side effect of ASP treatment is coagulopathy, especially deficiency of antithrombin III (ATIII). The aim of this study was to analyze the relationship between ASP and ATIII activities and the possibility of ATIII activity use in an indirect ASP activity assessment. ASP and ATIII activity was measured in 76 children with ALL treated according to the ALL IC BFM 2002 protocol. A correlation between ASP and ATIII activities was found (R=-0.43, P=0.0001). ROC curve analysis revealed some utility regarding the determination of ATIII in identifying patients with low or undetectable ASP activity (area under the curve=0.87 [95% confidence interval, 0.77-0.96], P<0.0001 and 0.93 [95% confidence interval, 0.85-1.0], P<0.0001, respectively). Higher ATIII activity is associated with a higher probability of a decline in ASP activity. Examination of ATIII activity cannot replace a direct determination of ASP activity, but in the case of unavailability of the direct test, it can be a helpful surrogate parameter of drug activity.