scholarly journals Dynamic 3D chromosomal landscapes in acute leukemia

2019 ◽  
Author(s):  
Andreas Kloetgen ◽  
Palaniraja Thandapani ◽  
Panagiotis Ntziachristos ◽  
Yohana Ghebrechristos ◽  
Sofia Nomikou ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Three Dimensional ◽  
Dynamic Responses ◽  
Human Leukemia ◽  
Fusion Event ◽  
Pharmacological Agents ◽  
Chromatin Architecture ◽  
The Impact

ABSTRACTThree-dimensional (3D) chromatin architectural changes can alter the integrity of topologically associated domains (TADs) and rewire specific enhancer-promoter interactions impacting gene expression. Recently, such alterations have been implicated in human disease, highlighting the need for a deeper understanding of their role. Here, we investigate the reorganization of chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) using primary human leukemia specimens and its dynamic responses to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-Seq and CTCF ChIP-Seq datasets revealed widespread changes in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD “fusion” event being associated with loss of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data show that small molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation reduce specific 3D interactions associated with transformation. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.One Sentence Summary3D chromatin alterations in T cell leukemia are accompanied by changes in insulation and oncogene expression and can be partially restored by targeted drug treatments.

scholarly journals V(D)J-mediated Translocations in Lymphoid Neoplasms: A Functional Assessment of Genomic Instability by Cryptic Sites⋆

2002 ◽  
Vol 195 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Rodrig Marculescu ◽  
Trang Le ◽  
Paul Simon ◽  
Ulrich Jaeger ◽  
Bertrand Nadel
Keyword(s):  
T Cell ◽  
Genomic Instability ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Lymphoid Malignancies ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Normal Human ◽  
Hodgkin's Lymphomas ◽  
The Impact

Most lymphoid malignancies are initiated by specific chromosomal translocations between immunoglobulin (Ig)/T cell receptor (TCR) gene segments and cellular proto-oncogenes. In many cases, illegitimate V(D)J recombination has been proposed to be involved in the translocation process, but this has never been functionally established. Using extra-chromosomal recombination assays, we determined the ability of several proto-oncogenes to target V(D)J recombination, and assessed the impact of their recombinogenic potential on translocation rates in vivo. Our data support the involvement of 2 distinct mechanisms: translocations involving LMO2, TAL2, and TAL1 in T cell acute lymphoblastic leukemia (T-ALL), are compatible with illegitimate V(D)J recombination between a TCR locus and a proto-oncogene locus bearing a fortuitous but functional recombination site (type 1); in contrast, translocations involving BCL1 and BCL2 in B cell non-Hodgkin’s lymphomas (B-NHL), are compatible with a process in which only the IgH locus breaks are mediated by V(D)J recombination (type 2). Most importantly, we show that the t(11;14)(p13;q32) translocation involving LMO2 is present at strikingly high frequency in normal human thymus, and that the recombinogenic potential conferred by the LMO2 cryptic site is directly predictive of the in vivo level of translocation at that locus. These findings provide new insights into the regulation forces acting upon genomic instability in B and T cell tumorigenesis.

scholarly journals Incidence of Upper Extremity Deep Vein Thrombosis in Acute Leukemia and Effect on Mortality

TH Open ◽  
2020 ◽  
Vol 04 (04) ◽  
pp. e309-e317
Author(s):  
Christina Poh ◽  
Ann Brunson ◽  
Theresa Keegan ◽  
Ted Wun ◽  
Anjlee Mahajan
Keyword(s):  
Deep Vein Thrombosis ◽  
Acute Leukemia ◽  
Upper Extremity ◽  
Lymphoblastic Leukemia ◽  
Cox Proportional Hazards ◽  
High Risk Population ◽  
Vein Thrombosis ◽  
Increased Risk ◽  
Deep Vein ◽  
The Impact

AbstractThe cumulative incidence, risk factors, rate of subsequent venous thromboembolism (VTE) and bleeding and impact on mortality of isolated upper extremity deep vein thrombosis (UE DVT) in acute leukemia are not well-described. The California Cancer Registry, used to identify treated patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) diagnosed between 2009 and 2014, was linked with the statewide hospitalization database to determine cumulative incidences of UE DVT and subsequent VTE and bleeding after UE DVT diagnosis. Cox proportional hazards regression models were used to assess the association of UE DVT on the risk of subsequent pulmonary embolism (PE) or lower extremity deep vein thrombosis (LE DVT) and subsequent bleeding, and the impact of UE DVT on mortality. There were 5,072 patients identified: 3,252 had AML and 1,820 had ALL. Three- and 12-month cumulative incidences of UE DVT were 4.8% (95% confidence interval [CI]: 4.1–5.6) and 6.6% (95% CI: 5.8–7.5) for AML and 4.1% (95% CI: 3.2–5.1) and 5.9% (95% CI: 4.9–7.1) for ALL, respectively. Twelve-month cumulative incidences of subsequent VTE after an incident UE DVT diagnosis were 5.3% for AML and 12.2% for ALL. Twelve-month cumulative incidences of subsequent bleeding after an incident UE DVT diagnosis were 15.4% for AML and 21.1% for ALL. UE DVT was associated with an increased risk of subsequent bleeding for both AML (hazard ratio [HR]: 2.07; 95% CI: 1.60–2.68) and ALL (HR: 1.62; 95% CI: 1.02–2.57) but was not an independent risk factor for subsequent PE or LE DVT for either leukemia subtype. Isolated incident UE DVT was associated with increased leukemia-specific mortality for AML (HR: 1.42; 95% CI: 1.16–1.73) and ALL (HR: 1.80; 95% CI: 1.31–2.47). UE DVT is a relatively common complication among patients with AML and ALL and has a significant impact on bleeding and mortality. Further research is needed to determine appropriate therapy for this high-risk population.

Impact of Ethnicity On Incidence and Survival Among Adults with Acute Lymphoblastic Leukemia in the United States; Insights From 2005 SEER Data.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3069-3069
Author(s):  
Casey L O'Connell ◽  
Pedram Razavi ◽  
Roberta McKean-Cowdin ◽  
Malcolm C. Pike
Keyword(s):  
T Cell ◽  
B Cell ◽  
Ethnic Groups ◽  
Lymphoblastic Leukemia ◽  
The United States ◽  
Incidence Rates ◽  
The Us ◽  
Race Ethnicity ◽  
The Impact ◽  
Racial Ethnic

Abstract Abstract 3069 Poster Board III-6 Background Acute lymphoblastic leukemia (ALL) is an aggressive malignancy whose incidence declines through adolescence and then increases steadily with age. Prognosis appears to be inversely related to age among adults. We sought to explore the impact of race/ethnicity on incidence and survival among adults with ALL in the United States (US). Methods We examined trends in incidence and survival among adults with ALL in the US using the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) program which includes data from 17 SEER registries. We calculated the incidence rates for the most recent time period (2001-2005) because the classification for ALL subtypes was more complete during this time. For the survival analysis we used the data collected between 1975 and 2005. We categorized race/ethnicity into 5 mutually exclusive categories: non-Hispanic whites (NHW), Hispanic whites (HW), African Americans (AA), Asian/Pacific Islanders (API) and American Indians/Native Alaskans (AI/NA). Hispanic ethnicity was defined using SEER's Hispanic-origin variable which is based on the NAACCR Hispanic Identification Algorithm (NHIA); 11 patients dually coded as black and Hispanic were included in the AA group for our analyses. Few ALL cases were identified among AI/NA, so that group is not represented in the final analyses. We included ALL cases coded in the SEER registry using the International Classification of Disease for Oncology (ICD-0-3) as 9827-9829 and 9835-9837. We excluded cases of Burkitt's leukemia (n=228), cases that were not confirmed by microscopic or cytologic tests (n=132), cases that were reported only based on autopsy data (n=3) and cases whose race/ethnicity were unknown (n=20). The average annual incidence rates per 100,000 for 2001-2005, age-adjusted to the 2000 US standard population were calculated using SEER*Stat Version 6.4.4 statistical software. We used multivariate Cox hazard models stratified by SEER registry and age category to estimate the hazard ratios (HR) and 95% confidence intervals (95% CI) for relative survival of adult ALL cases across race/ethnicity, sex and cell of origin (B- or T-cell). All models were adjusted for the diagnosis era, and use of non-CNS radiation. The model also included an interaction term for age and diagnosis era. We performed a separate stratified analysis of the impact of race/ethnicity on survival within age subgroups (20-29, 30-39, 40-59, 60-69, 70+). Results The highest incidence rate (IR) of ALL was observed for HW (IR: 1.60; 95% CI: 1.43-1.79). HW had a significantly higher IR across all age categories as compared to the other racial/ethnic groups, while AA had the lowest IR. In particular, the observed rate of B-cell ALL among HW (IR 0.77; 95% CI 0.69-0.87) was more than twice that of NHW (IR: 0.29; 95% CI: 0.27-0.32) and more than three times the rate observed among AA (IR: 0.20; 95% CI: 0.15-0.26). In contrast, we did not observe statistically significant variability in the rates of T-cell ALL across race/ethnic groups (overall IR: 0.12; 95% CI: 0.11-0.14). Survival was significantly poorer among AA (HR: 1.26; 95% CI: 1.09-1.46), HW (HR: 1.21; 95% CI: 1.09-1.46), and API (HR: 1.18; 95% CI: 1.06-1.32) compared to NHW with all subtypes of ALL. Among adults younger than 40 with B-cell ALL, survival was significantly poorer among AA (HR: 1.60; 95% CI:1.021-2.429) and HW (HR: 1.53; 95% CI:1.204-1.943) with a non-signficant trend among API (HR: 1.22; 95% 0.834-1.755) compared to NHW. Survival differences between the different racial/ethnic groups were no longer statistically significant among adults with B-cell ALL over the age of 40. For T-cell ALL, survival was significantly poorer among AA (HR: 1.61; 95% CI: 1.22-2.10), HW (HR: 1.49; 95% CI: 1.14-1.93) and API (HR: 1.57; 95% CI: 1.13-2.13), as compared to NHW. A similar survival pattern by age (adults above and below age 40 years) was observed for T-cell as described for B-cell, with AA under 40 having a particularly dismal prognosis (HR: 2.89; 95% CI 1.96-4.17) compared to NHW. Conclusions The incidence rate of B-cell ALL among adults in the US is higher among HW than other ethnic groups. Survival is significantly poorer among AA and HW than among NHW under the age of 40 with B-cell ALL. Survival is also significantly poorer among AA, HW and API than among NHW with T-cell ALL in adults under 40. Survival trends appear to converge after the age of 40 among all racial/ethnic groups. Disclosures No relevant conflicts of interest to declare.

Infectious Central Venous Line Complications During Induction Therapy for Newly Diagnosed Acute Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4322-4322
Author(s):  
Rebecca Cook ◽  
Roger Berkow
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Acute Leukemia ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Wound Dehiscence ◽  
Newly Diagnosed ◽  
Central Venous ◽  
Central Lines ◽  
Picc Line

Abstract Abstract 4322 Introduction: Childhood acute leukemia treatment requires central venous lines (CVL) for instillation of chemotherapy and blood products. Ideally, a proper white cell count (WBC) and absolute neutrophil count (ANC) ensure proper healing of CVLs, but this is challenging in children with acute leukemia. We sought to investigate the CVL complication rate in newly diagnosed children with acute leukemia during their induction therapy, and determine if the degree of neutropenia at the time of CVL placement correlated with the number of CVLs lost due to infection, wound dehiscence, or thrombosis. Methods: We conducted a retrospective chart review of children diagnosed with leukemia between January 2007 and December 2009 and recorded leukemia type, WBC and ANC at diagnosis and at the time of CVL placement, the type of CVL placed (external line, subcutaneous port) or placement of peripherally inserted central (PICC) line. We recorded complications, including infection, line malfunction, wound dehiscence, and thrombosis within their induction therapy phase. Results: Ninety-five children were evaluable, including 68 children with precursor B acute lymphoblastic leukemia (pre B ALL), 19 with acute myelogenous leukemia (AML), and 8 with T-cell acute lymphoblastic leukemia (T cell ALL). Ninety-eight CVLs were placed in 94 children (1 child died of complications of APML before initiation of therapy). There were 77 subcutaneous ports and 21 external lines placed. Eleven patients received PICC lines for various reasons (ex – sedation risk due to large mediastinal mass or altered mental status due to leukocytosis, coagulopathy, refractory thrombocytopenia, previously placed PICC line at outside hospital). ANC at the time of CVL insertion was reviewed: ANC<500 in 39 central lines, 500–1000 in 29 central lines, and >1000 in 30 central lines. Only 1 central line was removed due to wound dehiscence in a child with T cell ALL, and 2 central lines were removed for cellulitis in children with pre B ALL, and all these patients had ANC<500 at the time of line insertion. Two of the 98 central lines developed an associated thrombosis (1 CVL associated extensive arm venous thrombus and 1 external line with small atrial thrombus at tip of catheter), as opposed to 2 of the 11 PICC lines placed (both extensive arm venous thrombi). Seventeen positive blood cultures occurred during the first month of induction (15 from central lines and 2 from PICC lines), and all infections cleared with antibiotics except for 1 patient with PICC-associated venous thrombosis and persistent MRSA bacteremia. One subcutaneous port had to be revised after 3 days due to deep insertion and difficultly accessing; this child had ANCs<500 during each surgery and healed without complications. Three external lines were removed due to malfunction (2 with ANC<500, 1 with ANC 500–1000 at time of insertion). Conclusions: Nearly 40% of CVLs were placed in times of severe neutropenia (ANC<500), and only 3 were lost due to cellulitis or wound dehiscence. No CVL was lost due to persistent bacteremia compared to 1 PICC line. There was an increased incidence of thrombosis in PICC lines (2 of 11 placed) compared to external lines or ports (2 of 98 lines placed). We failed to see an increased risk of infection due to degree of neutropenia at the time of CVL insertion. Disclosures: No relevant conflicts of interest to declare.

Promotion and maintenance of leukemia by ERG

Blood ◽  
2011 ◽  
Vol 117 (14) ◽  
pp. 3858-3868 ◽  
Author(s):  
Shinobu Tsuzuki ◽  
Osamu Taguchi ◽  
Masao Seto
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Chromosome 21 ◽  
Human Leukemia ◽  
General Role ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Adult Leukemia

Abstract The Ets-related gene (ERG) located on human chromosome 21 encodes a transcription factor and is thought to be causally related to Down syndrome–associated acute megakaryocytic leukemia in childhood. In clinical adult leukemia, however, increased expression of ERG is indicative of poor prognosis in T-cell acute lymphoblastic leukemia and cytogenetically normal acute myeloid leukemia, although the involvement of ERG in the development of adult leukemia remains elusive. Here, we show that forced expression of ERG in adult BM cells alters differentiation and induces expansion of T and erythroid cells and increases frequencies of myeloid progenitors in mouse BM transplantation models. The expanded T cells then develop T-cell acute lymphoblastic leukemia after acquisition of mutations in the Notch1 gene. Targeted expression of ERG into B cells also altered differentiation and promoted growth of precursor B cells. Overall, these findings suggest a general role of ERG in promoting growth of adult hematopoietic cells in various lineages. In line with this, shRNA-mediated silencing of ERG expression attenuated growth of human leukemia cell lines of various lineages. Thus, ERG is capable of promoting the development of leukemia and is crucial for its maintenance.

scholarly journals Low Prevalence of T-Cell Lymphoblastic Leukemia/Lymphoma in an Adult Hispanic Population: A Report of the Acute Leukemia Working Group (GTLA)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Luis Felipe Rubalcava-Lara ◽  
Emmanuel Almanza Huante ◽  
Roberta Demichelis ◽  
Juan Rangel-Patiño ◽  
Andres Gomez-De Leon ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Rank Test ◽  
Induction Treatment ◽  
P Value ◽  
Cell Transplant ◽  
Hispanic Population

Introduction: The proportion of Acute lymphoblastic T cell leukemia/lymphoma (T-ALL/LBL) in Latinamerica (LA) is about 13% [Quiroz, 2018], compared with 25% of other publications [Litzow,2015]. In the largest leukemia series of adult Mexican population, the incidence of T-ALL was merely 2.9% with a -SG. The main objective of this study was to describe the epidemiological characteristic and survival of T-ALL in 4 reference oncology centers in Mexico. Methods: Retrospective cohort study from 2014 to 2019 in all consecutive, newly diagnosed T-ALL patients defined by flow cytometry (FC). The primary end point was to assess the survival of T-ALL in a Hispanic population. Baseline characteristics were grouped in tables and summarized as medians and ranges. Sub-groups were compared using chi-square test for binary variables and Mann-Whitney U test for quantitative variables. The Overall Survival (OS) analysis was made using Kaplan-Meier curves and comparison between groups was performed using the log-rank test with a significant P value less than 0.05 with 95% confidence interval. Results: A total of 47 patients were identified, which represent 11.1% of all acute leukemia the median of age was 30 years. The 83.7% being identified in the adolescent young-adult (AYA) group. Counterintuitively a 44.9% had a previous comorbidity (diabetes, hypertension, dyslipidemia) considering the range of age. The 85% had a low risk of mortality using the modified Charlson index, the median count of leukocytes was 36 x 109 (range 6.78-117) and 28% presented with initial hyperleukocytosis, the median LDH was 605 UI/l (range 343-1451). Applying the European Group for the Immunological Classification of Leukemias criteria: 28% were cortical T, 41.7% were mature and approximately 30% were be classified as early. Applying the early T-P (ETP) definition a total of 10 cases were identified (22.2% prevalence). The use of hyperCVAD and pediatric inspired regimens shared the same rate (41.3%), strikingly there is still a 17.4% of patients that received other type of chemotherapy for diverse reasons (economic, shortage of treatment, patient or physician preference) being the CHOP-inspired schemes the most used. The rate of complete response (CR) at 4 weeks after induction was 68.2% with 54.2% having a negative minimal residual disease (MRD). After 8 weeks a total of 34 (77.3%) patients achieved CR, with 63.6% and 66.7 % maintaining negative MRD at 16 weeks and after consolidations, respectively. Only 38.3% were able to complete the full induction treatment without a dose adjustment due to toxicity. A total of 8 (19.5%) were refractory to initial frontline treatment and eventually 23 (60.5%) relapsed, with a total of 10 patients presenting with CNS infiltration at relapse. A total of 6 patients received an allogenic stem cell transplant (ASCT), with 4 of them being alive and in CR at the 100 days cutoff. The median OS was 16 months (CI 95% 11.4-21.09) and 38.8% of our population was alive at the 24 months cutoff. This time period was drastically reduced for the non-AYA population who had a OS of 7.69 months (CI 95% 0-21.24) and 21.9% a 24 months progression free survival (PFS), compared with 16.6 months (CI 7.41-25.81) and 41.6% 24 months PFS. In the univariate analysis refractoriness to induction (p 0.039) and higher number of cycles (p 0.02) were associated with worse outcome. Conclusions: The T-ALL predominantly affects AYA populations while its incidence in our country appears to be lower even in large oncologic concentration centers. The proportion of ETP was slightly higher than that reported in other studies. Lower CR rates with a low frequency of ASCT in comparison to those reported in high income countries was observed, probably associated with the delay in implementation of pediatric-inspired regimens and lack of access to ASCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals The impact of immunological and biomolecular investigations on the outcome of children with acute lymphoblastic leukemia - experience of IIIrd Paediatric Clinic Timisoara

2018 ◽  
Vol 26 (1) ◽  
pp. 77-85
Author(s):  
Cristian Jinca ◽  
Carmen Angela Maria Petrescu ◽  
Estera Boeriu ◽  
Andrada Oprisoni ◽  
Loredana Balint-Gib ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Genetic Diagnosis ◽  
Supportive Therapy ◽  
Entire Group ◽  
Pediatric Clinic ◽  
Pcr Method ◽  
The Impact

Abstract Introduction. The unsatisfactory results of the survival in patients with acute lymphoblastic leukemia (ALL) until 2000 in our center have led us to improve the approach of diagnosis and therapy. Since 2003 in all patients the following have been performed: flow cytometry, conventional genetic diagnosis, FISH (fluorescent in situ hybridization), and molecular biology. Objectives. Our aims were to identify solutions to increase patients’ survival. Patients and method. It is a single-center, retrospective study of 136 patients with ALL treated at 3rd Pediatric Clinic of Timisoara, over a period of 10 years (2003-2012), where survival was assessed. Results. Morphologically, 86% of the patients were L1 type, 13% L2 type and 1% L3 type. Flow citometry revealed that 68% were ALL with B precursors, and 19% with T immunophenotype. Acute leukemia with mixed phenotype (biphenotypic) was identified in 2.3% of patients and 10.7% of the forms were acute leukemia with myeloid markers. In 27.7% of patients, mutations were detected by the RT-PCR method, the most commonly identified was TEL-AML1 (ETV6- RUNX1) accounting for 12.7% of the cases. Relapse-free survival at 5 years for the entire group was 59%, and for the group treated between 2008 and 2012 it was 72%. Conclusion. Our analysis confirms the decisive value of laboratory investigations for the prognosis and improvement of supportive therapy.

scholarly journals Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia

2020 ◽  
Vol 52 (4) ◽  
pp. 388-400 ◽  
Author(s):  
Andreas Kloetgen ◽  
Palaniraja Thandapani ◽  
Panagiotis Ntziachristos ◽  
Yohana Ghebrechristos ◽  
Sofia Nomikou ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Three Dimensional ◽  
Cell Acute Lymphoblastic Leukemia

Role of cranial radiotherapy for childhood T-cell acute lymphoblastic leukemia with high WBC count and good response to prednisone. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster groups.

1997 ◽  
Vol 15 (8) ◽  
pp. 2786-2791 ◽  
Author(s):  
V Conter ◽  
M Schrappe ◽  
M Aricó ◽  
A Reiter ◽  
C Rizzari ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Group Versus ◽  
Rank Test ◽  
Intrathecal Methotrexate ◽  
Intrathecal Therapy ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Wbc Count ◽  
The Impact

PURPOSE The ALL-BFM 90 and AIEOP-ALL 91 studies share the same treatment backbone and have 5-year event-free survival (EFS) rates close to 75%. This study evaluated the impact of differing presymptomatic CNS therapies in T-cell acute lymphoblastic leukemia (T-ALL) patients with a good response to prednisone (PGR) according to WBC count and Berlin-Frankfurt-Münster (BFM) risk factor (RF). PATIENTS A total of 192 patients (141 boys; median age, 7.5 years) with T-ALL, PGR, RF less than 1.7, and no CNS leukemia diagnosed between 1990 and 1995 were enrolled onto the ALL-BFM 90 (n = 123) or AIEOP-ALL 91 (n = 69) study. Presymptomatic CNS therapy consisted of cranial radiation (CRT) and intrathecal methotrexate (I.T. MTX) (11 doses) in the BFM study and of extended triple intrathecal therapy (T.I.T.) (17 doses) in the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) study. Patients were divided into a low-WBC group (WBC count < 100,000/microL) and a high-WBC group (WBC count > 100,000/microL). EFS was compared using the log-rank test. RESULTS For patients treated with CRT and I.T. MTX (BFM group), the 3-year EFS rate was 89.8% (SE = 3.5) for 99 patients in the low-WBC group versus 81.9% (SE = 8.2) in the high-WBC group (difference not significant). Conversely, for patients treated with T.I.T. alone (AIEOP group), the EFS rate was 80.6% (SE = 5.6) in 55 patients with a low WBC count versus 17.9% (SE = 11.0) in 14 patients with a high WBC count (P < .001). CONCLUSION These data suggest that CRT may not be necessary in PGR T-ALL patients with a WBC count less than 100,000/microL; on the contrary, in patients with a high count, extended T.I.T. may be inferior to CRT and I.T. MTX.

scholarly journals Methylthioadenosine phosphorylase deficiency in acute leukemia: pathologic, cytogenetic, and clinical features

Blood ◽  
1988 ◽  
Vol 71 (6) ◽  
pp. 1568-1573 ◽  
Author(s):  
ST Traweek ◽  
MK Riscoe ◽  
AJ Ferro ◽  
RM Braziel ◽  
RE Magenis ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
T Cell ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosome 9 ◽  
Polyamine Metabolism ◽  
Acute Leukemias ◽  
Karyotypic Analysis ◽  
Male Predominance ◽  
Methylthioadenosine Phosphorylase

Abstract Blast cells from 100 cases of acute leukemia were evaluated for the presence of methylthioadenosine phosphorylase (MTAase), an enzyme important in polyamine metabolism. Ten cases (10%) had undetectable levels of MTAase activity. Of the 10, 5 had acute lymphoblastic leukemia (ALL), 3 had acute myeloblastic leukemia (AML) and 2 expressed mixed lineage markers as determined by immunophenotyping. A relatively high frequency (38%) of MTAase deficiency was seen in ALL of T-cell origin. Nonmalignant hematopoietic cells from three patients with MTAase-deficient leukemias had readily detectable enzyme activity. Chromosomal abnormalities were detected in four of the seven MTAase- deficient cases in which karyotypic analysis was performed. No consistent karyotypic defect was apparent, and only one case displayed changes in chromosome 9, the putative location of the MTAase structural gene. The clinical findings among the enzyme-deficient cases were unremarkable except that all patients were male (P less than .01). Only one patient had “lymphomatous” features. We conclude that MTAase deficiency occurs in a wide variety of acute leukemias, that the lack of enzyme activity is specific to the malignant cells, and that an increased incidence occurs in ALL of T-cell origin. Furthermore, no specific gross chromosomal abnormality is associated with the enzyme deficiency. The marked male predominance in patients with MTAase- deficient acute leukemias suggests involvement of the X chromosome in the loss of enzyme activity. The absence of MTAase in some leukemias may be therapeutically exploitable.

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