Re-Evaluate of DNA Index Among the Childhood Acute Lymphoblastic Leukemia

Lymphoblastic Leukemia ◽

Generalized Additive Models ◽

Threshold Effect ◽

Adverse Outcomes ◽

Additive Models ◽

Dna Index ◽

Childhood All ◽

Abstract Background This study was aimed to re-evaluate the value of DNA index(DI) among pediatric acute lymphoblastic leukemia (ALL) with the recent chemotherapy protocols.Methods Retrospective study were analysis among pediatric ALL patients from the TAGET dataset.Result Totally, 1,668 eligible pediatric patients were enrolled in this study. Of them, 993 are male and 675 are female with a median age of 7.6 years old. The median follow-up for those patients was 7.7 years (range 0.1-15.7 years). The probability of 10-year EFS and OS were reported to be 68.3±2% and 79.6±2%, respectively. Multivariate analysis showed that DI was significantly associated with better EFS and OS. The threshold effect of DI on poor outcome was significant after adjusting for potential confounders. The adjusted regression coefficient (Log RR) was 0.7 (95%CI 0.1-3.2, P=0.597) for DI <1.1 while 8.8 (95%CI 1.4-56.0, P=0.021) for DI≥1.2 and 0.0 (95%CI 0.0-0.8, P=0.041) for 1.1≤DI<1.2. Generalized additive models revealed that the lowest rates of the adverse outcomes estimated to occur among DI between 1.1 and 1.2. Conclusion For those childhood ALL treated with recent chemotherapy protocols, the DI between 1.1 and 1.2 can serve as a significant cut-point discriminating the risk group, which indicated an independent prognostic factor.

DNA index as prognostic factor in childhood acute lymphoblastic leukemia in the COG-TARGET database

BMC Cancer ◽

10.1186/s12885-021-08545-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Kun-yin Qiu ◽

Xiong-yu Liao ◽

Zhan-wen He ◽

Ruo-hao Wu ◽

Yang Li ◽

...

Keyword(s):

Prognostic Factor ◽

Fusion Gene ◽

Lymphoblastic Leukemia ◽

Generalized Additive Models ◽

Threshold Effect ◽

Adverse Outcomes ◽

Additive Models ◽

Dna Index ◽

Childhood All

Abstract Background This study was aimed to evaluate the value of DNA index(DI) among pediatric acute lymphoblastic leukemia (ALL) treated on Children’s Oncology Group (COG) protocols between 2000 and 2015. Methods Retrospective study were analysis among pediatric ALL patients from the TARGET dataset. Result Totally, 1668 eligible pediatric patients were enrolled in this study. Of them, 993 are male and 675 are female with a median age of 7.6 years old. The median follow-up for those patients was 7.7 years (range 0.1–15.7 years). The probability of 15-year EFS and OS were reported to be 67.5 ± 3.1% and 78.3 ± 2.5%, respectively. BCR/ABL1 fusion gene affected the early treatment response and the survival of childhood ALL. Moreover, those patients with ETV6/RUNX1 fusion gene were also significantly associated with better EFS (HR = 0.6, 95% CI 0.4–0.8, P = 0.003) and OS (HR = 0.3, 95%CI 0.2–0.5, P < 0.001) compared to patients with no ETV6/RUNX1. On the contrary, BM NR on Day+ 29 showed a significant decrease in EFS (HR = 3.1, 95%CI 2.1–4.5, P < 0.001) and OS (HR = 1.7, 95%CI 1.1–2.8, P = 0.026). Multivariate analysis showed that DI was significantly associated with better EFS and OS. The threshold effect of DI on poor outcome was significant after adjusting for potential confounders. The adjusted regression coefficient (Log RR) was 0.7 (95%CI 0.1–3.2, P = 0.597) for DI < 1.1 while 8.8 (95%CI 1.4–56.0, P = 0.021) for DI ≥ 1.2 and 0.0 (95%CI 0.0–0.8, P = 0.041) for 1.1 ≤ DI < 1.2. Generalized additive models revealed that the lowest rates of the adverse outcomes estimated to occur among DI between 1.1 and 1.2. Conclusion For those childhood ALL treated on COG protocols between 2000 and 2015, ETV6/RUNX1 and BM NR were closely related to the prognosis. Moreover, the DI between 1.1 and 1.2 can serve as a significant cut-point discriminating the risk group, which indicated a favourable prognostic factor.

Incidence and Clinical Relevance of TEL/AML1 Fusion Genes in Children With Acute Lymphoblastic Leukemia Enrolled in the German and Italian Multicenter Therapy Trials

Blood ◽

10.1182/blood.v90.2.571.571_571_577 ◽

1997 ◽

Vol 90 (2) ◽

pp. 571-577 ◽

Cited By ~ 5

Author(s):

Arndt Borkhardt ◽

Giovanni Cazzaniga ◽

Susanne Viehmann ◽

Maria Grazia Valsecchi ◽

Wolf Dieter Ludwig ◽

...

Keyword(s):

Fusion Gene ◽

Lymphoblastic Leukemia ◽

Prognostic Impact ◽

Dna Index ◽

Childhood All ◽

Pediatric All ◽

Aml1 Gene ◽

B Lineage ◽

The Impact

The molecular approach for the analysis of leukemia associated chromosomal translocations has led to the identification of prognostic relevant subgroups. In pediatric acute lymphoblastic leukemia (ALL), the most common translocations, t(9; 22) and t(4; 11), have been associated with a poorer clinical outcome. Recently the TEL gene at chromosome 12p13 and the AML1 gene at chromosome 21q22 were found to be involved in the translocation t(12; 21)(p13; q22). By conventional cytogenetics, however, this chromosomal abnormality is barely detectable and occurs in less than 0.05% of childhood ALL. To investigate the frequency of the molecular equivalent of the t(12; 21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankfurt-Münster (BFM) and Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) multicenter ALL therapy trials. We have analyzed 334 unselected cases of pediatric ALL patients consecutively referred over a period of 5 and 9 months, respectively. The overall incidence of the t(12; 21) in pediatric ALL is 18.9%. The 63 cases positive for the TEL/AML1 chimeric products ranged in age between 1 and 12 years, and all but one showed CD10 and pre-B immunophenotype. Interestingly, one case displayed a pre-pre–B immunophenotype. Among the B-lineage subgroup, the t(12; 21) occurs in 22.0% of the cases. Fifteen of 61 (24.6%) cases coexpressed at least two myeloid antigens (CD13, CD33, or CDw65) in more than 20% of the gated blast cells. DNA index was available for 59 of the 63 TEL/AML1 positive cases; a hyperdiploid DNA content (≥1.16) was detected in only four patients, being nonhyperdiploid in the remaining 55. Based on this prospective analysis, we retrospectively evaluated the impact of TEL/AML1 in prognosis by identifying the subset of B-lineage ALL children enrolled in the closed German ALL-BFM-90 and Italian ALL-AIEOP-91 protocols who had sufficient material for analysis. A total of 342 children were investigated for the presence of TEL/AML1 fusion gene and 99 cases (28.9%) were positive. The patients expressing the TEL/AML1 fusion mRNA appeared to have a better event-free survival (EFS) than the patients who lacked this chimeric product. Whereas three of the TEL/AML1 positive cases (3.0%) have relapsed to date, 27 patients without TEL/AML1 rearrangement (11.1%) suffered from relapse. To date, the only subset of B-lineage ALL with a favorable prognosis has been the hyperdiploid group (DNA index ≥1.16 <1.6). Our findings reinforce the need to include the molecular screening of the t(12; 21) translocation within ongoing prospective ALL trials to prove definitively its prognostic impact.

Incidence and Clinical Relevance of TEL/AML1 Fusion Genes in Children With Acute Lymphoblastic Leukemia Enrolled in the German and Italian Multicenter Therapy Trials

Blood ◽

10.1182/blood.v90.2.571 ◽

1997 ◽

Vol 90 (2) ◽

pp. 571-577 ◽

Cited By ~ 227

Author(s):

Arndt Borkhardt ◽

Giovanni Cazzaniga ◽

Susanne Viehmann ◽

Maria Grazia Valsecchi ◽

Wolf Dieter Ludwig ◽

...

Keyword(s):

Fusion Gene ◽

Lymphoblastic Leukemia ◽

Prognostic Impact ◽

Dna Index ◽

Childhood All ◽

Pediatric All ◽

Aml1 Gene ◽

B Lineage ◽

The Impact

Abstract The molecular approach for the analysis of leukemia associated chromosomal translocations has led to the identification of prognostic relevant subgroups. In pediatric acute lymphoblastic leukemia (ALL), the most common translocations, t(9; 22) and t(4; 11), have been associated with a poorer clinical outcome. Recently the TEL gene at chromosome 12p13 and the AML1 gene at chromosome 21q22 were found to be involved in the translocation t(12; 21)(p13; q22). By conventional cytogenetics, however, this chromosomal abnormality is barely detectable and occurs in less than 0.05% of childhood ALL. To investigate the frequency of the molecular equivalent of the t(12; 21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankfurt-Münster (BFM) and Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) multicenter ALL therapy trials. We have analyzed 334 unselected cases of pediatric ALL patients consecutively referred over a period of 5 and 9 months, respectively. The overall incidence of the t(12; 21) in pediatric ALL is 18.9%. The 63 cases positive for the TEL/AML1 chimeric products ranged in age between 1 and 12 years, and all but one showed CD10 and pre-B immunophenotype. Interestingly, one case displayed a pre-pre–B immunophenotype. Among the B-lineage subgroup, the t(12; 21) occurs in 22.0% of the cases. Fifteen of 61 (24.6%) cases coexpressed at least two myeloid antigens (CD13, CD33, or CDw65) in more than 20% of the gated blast cells. DNA index was available for 59 of the 63 TEL/AML1 positive cases; a hyperdiploid DNA content (≥1.16) was detected in only four patients, being nonhyperdiploid in the remaining 55. Based on this prospective analysis, we retrospectively evaluated the impact of TEL/AML1 in prognosis by identifying the subset of B-lineage ALL children enrolled in the closed German ALL-BFM-90 and Italian ALL-AIEOP-91 protocols who had sufficient material for analysis. A total of 342 children were investigated for the presence of TEL/AML1 fusion gene and 99 cases (28.9%) were positive. The patients expressing the TEL/AML1 fusion mRNA appeared to have a better event-free survival (EFS) than the patients who lacked this chimeric product. Whereas three of the TEL/AML1 positive cases (3.0%) have relapsed to date, 27 patients without TEL/AML1 rearrangement (11.1%) suffered from relapse. To date, the only subset of B-lineage ALL with a favorable prognosis has been the hyperdiploid group (DNA index ≥1.16 <1.6). Our findings reinforce the need to include the molecular screening of the t(12; 21) translocation within ongoing prospective ALL trials to prove definitively its prognostic impact.

“SOCIOECONOMIC FACTORS AFFECTING SURVIVAL IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA FROM NORTH-EAST INDIA”

10.36106/ijsr/0820971 ◽

2020 ◽

pp. 1-3

Author(s):

Partha Sarathi Roy ◽

Munlima Hazarika ◽

Rakesh Kumar Mishra ◽

BhargabJyoti Saikia ◽

Gaurav Kumar

Keyword(s):

Overall Survival ◽

Developing Countries ◽

Socioeconomic Factors ◽

Lymphoblastic Leukemia ◽

Childhood All ◽

Female Ratio ◽

Risk Of Death ◽

Lower Socioeconomic ◽

Acute lymphoblastic leukemia (ALL) is a highly curable childhood cancer with a survival rate of nearly 80% in developed countries but is around 45% in developing countries. This retrospective study analyzed the association between demographic and socioeconomic factors with survival in pediatric ALL. All confirmed cases of pediatric ALL (age <18 years) registered at Dr. B Borooah Cancer Institute between 2010 to 2017 were analyzed using data collected from hospital-based cancer registry and case records. Seventy-five confirmed cases of pediatrics ALL were eligible for the study. The median age of presentation was six years with a male: female ratio 1.9:1. Overall survival at 4-years was 43.8%, with a median survival of 25 months. A trend for higher 4-year overall survival was seen in female children (54.1% versus 37.9%, p=0.097). Patients from rural areas (44% versus 39.5%, p=0.308), with higher maternal education (83.3% versus 41.1%, p=0.161) and patients who did not abandon treatment (49.1% versus 31.2%, p=0.497) had better survival, but the differences were not significant. Four years overall survival in upper-middle, lower-middle, upper-lower, and lower class were 85.7%, 74.9%, 38.1%, and 7.7% respectively (upper-middleversus lower socioeconomic class, p=0.0001).Multivariate analyses confirmed a statistically significant relationship between socioeconomic status and survival, with the upper-middle group had a 90% decreased risk of death compared to the lower socioeconomic group. There is an urgent need for a proper definition of the problems of childhood ALL to introduce appropriate policies for improving survival in developing countries.

Three-Drug Induction and BFM-Type Intensive Consolidation Chemotherapy for Treatment of Standard Risk Childhood Acute Lymphoblastic Leukemia Defined Also by DNA index. The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) Study ALL-9501.

Blood ◽

10.1182/blood.v104.11.1951.1951 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1951-1951

Author(s):

Maurizio Arico’ ◽

Valentino Conter ◽

Maria Grazia Valsecchi ◽

Marie France Pinta Boccalatte ◽

Elena Barisone ◽

...

Keyword(s):

Bone Marrow ◽

Lymphoblastic Leukemia ◽

Malignant Neoplasm ◽

Small Subset ◽

Unrelated Donor ◽

Minimal Risk ◽

Dna Index ◽

Standard Risk

Abstract In this study, we tried to select a very small subset of children with acute lymphoblastic leukemia (ALL) at minimal risk of treatment failure - identified to not only by early response in vivo, one of the strongest predictors in the I-BFM-SG experience, but also by age, blood count and in particular high DNA content - which we treated with a reduced-intensity BFM schedule. The AIEOP-ALL 9501 study enrolled patients with standard-risk (SR) ALL, defined as: <20,000 WBC/mm3, age 1 to <6 years, non-T immunophenotype, DNA index between 1.16 and 1.6, non t(9;22), no extramedullary leukemia, good response to prednisone (PGR, defined as <1,000/mmc blasts in the peripheral blood after 7 days of prednisone and one injection of IT-MTX), CR at the end of induction therapy. Follow-up was updated at December,31st 2003 and median follow-up was 5.9 years. Treatment consisted of a modified BFM schedule: 3-drug (VCR + PDN + Erwinia ASP), 43-day induction, no phase IB, 4x2 g/m2 MTX, reinduction with protocol II followed by 6MP+MTX continuation therapy up to 2 years; CNS directed therapy consisted of IT-MTXx18. Between May 95 and August 2000, 137 patients were identified as SR (7.8% of the ALL-95 population), of whom 102 received the SR protocol and are here reported.Of them, 1 died in remission of septicemia, and 1 had developed a second malignant neoplasm (T-ALL after initial B-lineage ALL); 11 patients relapsed (bone marrow, n=8; central nervous system, n=1; marrow + testis, n=1; eye, n=1) and their re-treatment included chemotherapy only (n=3, 1 dead) or plus bone marrow transplant (n=8) either autologous (n=2) or allogeneic from matched (n=4, 1 dead) or partially matched (n=2) unrelated donor. The remaining 89 are in first CR; the probabilities (and related standard errors) of survival and event-free survival (EFS) were 97.0% (1.7) and 86.7% (3.5) at 5 years, 95.3% (2.4) and 86.7% (3.5) at 7 years, respectively. There was no difference in the outcome between the 56 females [7 events, 7-yrs EFS, 87.3 (4.5)] and the 46 males [6 events, 85.9 (5.4)]. Although most of the relapsed patients were rescued, the long-term EFS in this small, very selected group of patients remains inferior to expectance. Thus, alternative selection criteria, for instance related to minimal residual disease as in current AIEOP-ALL 2000, should be considered in order to address the issue of treatment reduction.

Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983

Blood ◽

10.1182/blood.v99.12.4257 ◽

2002 ◽

Vol 99 (12) ◽

pp. 4257-4264 ◽

Cited By ~ 129

Author(s):

Smita Bhatia ◽

Harland N. Sather ◽

Olga B. Pabustan ◽

Michael E. Trigg ◽

Paul S. Gaynon ◽

...

Keyword(s):

Brain Tumors ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Malignant Neoplasms ◽

Childhood All ◽

Second Neoplasms ◽

Increased Risk ◽

The Impact

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.

The Experience on Multiparametric Molecular Diagnostic Approach of Pediatric Acute Lymphoblastic Leukemia (ALL) in Greece.

Blood ◽

10.1182/blood.v108.11.4448.4448 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4448-4448

Author(s):

Agapi Parcharidou ◽

Constantina Sambani ◽

Christina Stavropoulou ◽

George Paterakis ◽

Chrysoula Belesi ◽

...

Keyword(s):

Genetic Polymorphism ◽

Lymphoblastic Leukemia ◽

Molecular Diagnostic ◽

Detoxifying Enzymes ◽

Dna Index ◽

Pediatric Acute Lymphoblastic Leukemia ◽

In Vitro Chemosensitivity ◽

Abstract The rate of success in the treatment of pediatric acute lymphoblastic leukemia (ALL) has been increased steadily during the last decades. The five years’ event free survival rate is nearly 80% for children with ALL. Attempts to boost cure rates further with the use of hematopoietic stem cell transplantation have improved for some but not all, subtypes of ALL. The best hope for continued progress lies in a better understanding of the pathogenesis, the basis of resistance to chemotherapy, and finally better organized clinical trials. The present study has been based on organizing and exploring new clinical correlations among clinical data obtained from molecular genetic profile, in vitro chemosensitivity and genetic polymorphisms of detoxifying enzymes. During the last 3 years 43 newly diagnosed ALL patients, 27 boys and 16 girls, aged 23 months to 14 years old were included in this study. Bone marrow and/or peripheral blood samples were studied for karyotyping aberrations. The presence of the specific translocations t(12;21), t(9;22), t(4;11) and t(1;19) was investigated using RT-PCR and FISH. Furthermore, FISH was also used for the detection 9p deletions and MLL rearrangements. Immunophenotype of blasts and DNA index were studied by flow cytometry. In vitro chemosensitivity studies were performed by the MTT assay (ELISA).The GSTT1 genetic polymorphism (null genotype) was detected by multiplex PCR and NQ1 genetic polymorphism was detected by PCR -RFLPs. A cytogenetic/molecular result was achieved in 39/43 patients. Structural or numerical aberrations were detected in 7/39 patients. 9/39 patients were positive for the TEL/AML1 (23%) and 3/39 for the BCR/ABL fusion genes. One patient showed only one MLL allele, no patient had MLL rearrangement and 5/19 patients presented 9p deletion. A null GSTT1 genotype was observed in 5/43children (11,62%) and 14/43 patients were heterozygotes for NQ1(32,5%). 8/36 patients presented in vitro chemoresistance and 8/43 patients had DNA index >1 (18,6%).In our series of patients the frequency of t(12;21) does not seem to differ significantly from the literature data. The patients who showed chemoresistance had also unfavorable prognostic markers according to cytogenetic/molecular diagnostic data or clinical characteristics. The number of the patients is low to correlate detoxifying enzymes to toxicity or response during treatment. The multiparametric diagnostic approaches in pediatric ALL seem to be of great importance in diagnosis and tailored therapy leading to high rates of cure. Our center’s effort is the optimal characterization of the pediatric ALL profile in Greece by the use of multiparametric diagnostic methods targeting a better outcome.

Low-dose versus high-dose methotrexate during remission induction in childhood acute lymphoblastic leukemia (Protocol 81-01 update)

Blood ◽

10.1182/blood.v78.10.2514.bloodjournal78102514 ◽

1991 ◽

Vol 78 (10) ◽

pp. 2514-2519 ◽

Cited By ~ 1

Author(s):

CM Niemeyer ◽

RD Gelber ◽

NJ Tarbell ◽

M Donnelly ◽

LA Clavell ◽

...

Keyword(s):

Low Dose ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

Remission Induction ◽

High Dose ◽

Childhood All ◽

To Receive

We evaluated event-free survival (EFS) and leukemia-free interval (LFI) of children treated for acute lymphoblastic leukemia (ALL). Patients were randomized to receive either a low dose or high dose of methotrexate (MTX) as a single agent at the time of diagnosis. Five days later, multidrug therapy was begun. We assessed the early antileukemic efficacy of the two doses of MTX, as well as toxicity and long-term efficacy. An increase in cell kill, as indicated by a larger decrease in the percentage of viable cells in the bone marrow between days 0 and 5, was observed for the high-dose MTX group when compared with the low-dose MTX group (P = .04). At 7.1 years of median follow- up, the 38 children randomized to receive high-dose MTX had a better EFS and LFI compared with the 39 patients randomized to receive low- dose MTX. The 7-year percentages (+/- SE) for EFS were 82% +/- 6% for high-dose MTX and 69% +/- 7% for low-dose MTX (P = .13). The 7-year percentages for LFI were 91% +/- 5% and 69% +/- 7%, respectively (P = .01). We recommend that high-dose MTX be considered as an effective addition to induction therapy in childhood ALL.

The Adherence to MRD Time Points Is a Significantly Prognostic Predictor in an MRD-Directed Therapy for Childhood Acute Lymphoblastic Leukemia in Taiwan

Blood ◽

10.1182/blood-2019-124432 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3813-3813

Author(s):

Hsi-Che Liu ◽

Ting-Chi Yeh ◽

Tang-Her Jaing ◽

Shih-Hsiang Chen ◽

Chih-Cheng Hsiao ◽

...

Keyword(s):

Treatment Outcomes ◽

Lymphoblastic Leukemia ◽

Childhood All ◽

Prognostic Predictor ◽

Time Points ◽

Cns Relapse ◽

Total Therapy ◽

Time Point

Backgrounds and Purposes Minimal residual disease (MRD) monitoring has been proved to be the most important prognostic predictor in childhood acute lymphoblastic leukemia (ALL). The nationwide TPOG-ALL-2013 protocol (TPOG-2013), adapted from the St. Jude Total Therapy XV Study and Total Therapy XVI Study, was launched since January 2013. This is the first MRD-directed protocol for treatment of childhood ALL in Taiwan. Here, we report the improved treatment outcomes and the impacts of adherence to MRD time points. Patients and Methods Totally, 402 patients aged between 1-18 years and diagnosed before December 31, 2018, who had MRD monitoring at the major central laboratory (Chang Gung Memorial Hospital-Linkou), were enrolled with the last follow-up on June 30, 2019. According to TPOG-2013, two MRD measurements were scheduled on days 15-19 of induction (MRD1 time point, TP1) and days 35-42, end of induction (MRD2 time point, TP2) to make the definitive risk stratification to guide subsequent therapy. The methodologies of MRD measurement included multicolor flow cytometry for leukemia-associated immunophenotypes (LAIP) (82.3% of TPOG-2013 cohort), qPCR assay for clonally rearranged antigen-receptor genes (Ig/TCR) if no LAIP (12.5%). Since January 2018, reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) was applied to patients carrying fusion transcripts (5.2%) of TCF3-PBX1, ETV6-RUNX1, BCR-ABL1, KMT2A-AFF1 (AF4) and KMT2A-MLLT3. The clinical features and outcomes of patients treated with TPOG-2013 were compared with those of 1,300 patients treated with the previous TPOG-ALL-2002 protocol (TPOG-2002), which did not integrate the MRD monitoring. Results The median follow-up time of the 402 patients of TPOG-2013 cohort was 32.5 months (range, 1.0-79.2 months). There were no significant differences in gender, age, WBC counts, and lineage at diagnosis between the patients treated with TPOG-2002 and TPOG-2013. However, based on the MRD data, the percentages of patients assigned to each risk group of TPOG-2013 was statistically differed from those of TPOG-2002 (P< 0.0001). The 5-year event-free survival (EFS) (% ± SE) was significantly improved from 78.1 ± 1.2 of TPOG-2002 to 85.4 ± 2.5 of TPOG-2013 (P< 0.0001). Further, the cumulative incidences (% ± SE) of isolated CNS relapse and any CNS relapse significantly decreased from 4.0 ± 0.5 to 0.3 ± 0.3 (P= 0.001) and from 5.8 ± 0.7 to 1.2 ± 0.9 (P= 0.001), respectively. The issue of non-adherence to MRD monitoring emerged since the implementation of MRD-directed TPOG-2013. For further analysis, 321 (80%) patients with exact adherence (EA) to both TPs were assigned as MRD EA group; 80 (20%) patients who were non-adherence (NA) to either one of TPs as MRD NA group; and one patient died between the two TPs was excluded for the comparative outcome analysis. The rate of non-adherence decreased significantly from 26.5% in 2013 to 2.4% in 2018. The major causes of non-adherence for both TPs were delaying MRD monitoring due to neutropenic fever and documented infections. In MRD EA group, 12.5% of patients were upgraded to higher-risk treatment groups based on their MRD results. The MRD NA group had older age (≥ 10 years), lower standard-risk and lower incidence of ETV6-RUNX1 compared with MRD EA group. There were significant differences in outcomes between MRD EA and MRD NA groups: the 5-year EFS were 89.4 ± 2.4 and 71.9 ± 7.4, respectively (P= 0.0005), overall survival (OS) were 90.9 ± 2.1 and 75.6 ± 5.8, respectively (P= 0.0003), and the cumulative incidence of isolated CNS relapse were 0 and 1.4 ± 1.3, respectively (P= 0.048) (Figure 1). In multivariate analysis, older age (≥ 10 years), higher WBC count (≥ 50 × 109/L) at diagnosis and MRD non-adherence were independent predictors for inferior EFS. In addition to these three factors, a higher-risk classification also predicted an inferior OS (Figure 2). Conclusions Contemporary MRD-directed therapy has improved the treatment outcomes of childhood ALL in Taiwan. The adherence to MRD time points remains a significantly prognostic predictor in the era of MRD-guided treatment. Disclosures No relevant conflicts of interest to declare.

Genomic Analyses of Pediatric Acute Lymphoblastic Leukemia Ph+ and Ph-Like—Recent Progress in Treatment

International Journal of Molecular Sciences ◽

10.3390/ijms22126411 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6411

Author(s):

Agnieszka Kaczmarska ◽

Patrycja Śliwa ◽

Joanna Zawitkowska ◽

Monika Lejman

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Targeted Therapies ◽

Lymphoblastic Leukemia ◽

Childhood All ◽

Pediatric Acute Lymphoblastic Leukemia ◽

Genomic Analyses ◽

Pediatric acute lymphoblastic leukemia (ALL) with t(9;22)(q34;q11.2) is a very rare malignancy in children. Approximately 3–5% of pediatric ALL patients present with the Philadelphia chromosome. Previously, children with Ph+ had a poor prognosis, and were considered for allogeneic stem cell transplantation (allo-HSCT) in their first remission (CR1). Over the last few years, the treatment of childhood ALL has significantly improved due to standardized research protocols. Hematopoietic stem cell transplantation (HSCT) has been the gold standard therapy in ALL Ph+ patients, but recently first-generation tyrosine kinase inhibitor (TKI)-imatinib became a major milestone in increasing overall survival. Genomic analyses give the opportunity for the investigation of new fusions or mutations, which can be used to establish effective targeted therapies. Alterations of the IKZF1 gene are present in a large proportion of pediatric and adult ALL Ph+ cases. IKZF1 deletions are present in ~15% of patients without BCR-ABL1 rearrangements. In BCR-ABL1-negative cases, IKZF1 deletions have been shown to have an independent prognostic impact, carrying a three-fold increased risk of treatment failure. The prognostic significance of IKZF1 gene aberrations in pediatric ALL Ph+ is still under investigation. More research should focus on targeted therapies and immunotherapy, which is not associated with serious toxicity in the same way as classic chemotherapy, and on the improvement of patient outcomes. In this review, we provide a molecular analysis of childhood ALL with t(9;22)(q34;q11.2), including the Ph-like subtype, and of treatment strategies.