scholarly journals Clinical characteristics and outcomes of patients with pediatric acute lymphoblastic leukemia after induction of chemotherapy: a pilot descriptive correlational study from Palestine

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ramzi Shawahna ◽  
Sultan Mosleh ◽  
Yahya Odeh ◽  
Rami Halawa ◽  
Majd Al-Ghoul
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Blood Cells ◽  
Clinical Characteristics ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
P Value ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All

Abstract Objective Pediatric acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer among children. This study was conducted to describe and correlate the clinical characteristics and outcomes of treatment of patients with pediatric ALL in the main referral hospital in Palestine. Results Complete data of 69 patients were included in this analysis. The majority (79.7%) of the patients had B-ALL phenotype. After induction chemotherapy, remission was experienced by the vast majority of the patients and 5 (7.2%) experienced relapses. Cytogenetics for patients with B-ALL phenotype indicated that 10 (18.2%) patients had t(12, 21) translocation, 5 (9.1%) had hyperdiploidy, 4 (7.3%) had t(1, 19) translocation, and 2 (3.6%) had t(9, 22) translocation. The initial white blood cells (p value < 0.001), absolute neutrophils (p value = 0.011), and hemoglobin (p value < 0.001) were significantly lower in patients with B-cell ALL. Platelet counts were significantly lower (p value = 0.012) in patients with splenomegaly and those with bleeding symptoms (p value = 0.008). Presence of palmar pollar was positively associated (p value = 0.035) with T-cell ALL. Presence of hepatomegaly was positively associated (p value < 0.001) with splenomegaly.

scholarly journals Clinical Characteristics and Outcome After Induction of Chemotherapy in Pediatric Acute Lymphoblastic Leukemia: A Descriptive and Correlational Study From the West Bank of Palestine

2020 ◽  
Author(s):  
Ramzi Shawahna
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Induction Chemotherapy ◽  
Clinical Characteristics ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
P Value ◽  
Published Data ◽  
Bone Marrow Biopsies ◽  
Progress Notes ◽  
Pediatric All

Abstract BackgroundPediatric acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer among children. This study was conducted to describe and correlate the clinical characteristics and outcomes of treatment of patients with pediatric ALL in the main referral hospital in Palestine. MethodsIn this single-center, retrospective, observational study, paper-based and electronic medical records of patients with pediatric ALL who received induction chemotherapy were reviewed. The sociodemographic variables, details of patient history, findings of physical examinations, daily progress notes, bone marrow biopsies, flow cytometry, and cytogenetics of patients were collected. ResultsComplete data of 69 patients were included in this analysis. The majority (79.7%) of the patients had B-ALL phenotype, 22 (31.9%) had abdominal pain, 37 (53.6%) had fever, 30 (43.5%) complained of bone pain, 50 (72.5%) had pallor, 9 (13.0%) had anorexia, 34 (49.3%) had hepatomegaly, 34 (49.3%) had splenomegaly, and 15 (21.7%) complained of bleeding symptoms. After induction chemotherapy, remission was experienced by the vast majority of the patients and 5 (7.2%) experienced relapse after receiving chemotherapy. The vast majority of the patients (96%) had CNS status 1, 1.4% had CNS status 2, and 2.9% had CNS status 3. Cytogenetics for patients with B-ALL phenotype indicated that 10 (18.2%) patients had t(12,21) translocation, 5 (9.1%) had hyperdiploidy, 4 (7.3%) had t(1,19) translocation, and 2 (3.6%) had t(9,22) translocation. The initial white blood cells (p value < 0.001), absolute neutrophils (p value = 0.011), and hemoglobin (p value < 0.001) were significantly lower for patients with B-cell ALL. Platelet counts were significantly lower (p value = 0.012) in patients with splenomegaly and those with bleeding symptoms (p value = 0.008). Presence of pollar was positively associated (p value = 0.035) with T-cell ALL. Presence of hepatomegaly was positively associated (p value < 0.001) with splenomegaly.ConclusionOverall, this study provides insights into the clinical characteristics and outcomes of induction chemotherapy in Palestinian patients with pediatric ALL. The characteristics of ALL among Palestinians were comparable to their peers in the region. The outcomes of induction chemotherapy were also comparable to other published data for ALL patients.

In-Vitro Efficacy of the Deoxyguanoside Analogs Forodesine (BCX-1777) and ARA-G in Pediatric Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2038-2038
Author(s):  
Irene Homminga ◽  
Michel C. Zwaan ◽  
Amel Seghouani ◽  
Chantal Y. Manz ◽  
Shanta Bantia ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Nucleoside Transporter ◽  
Nucleotide Synthesis ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Expression Levels ◽  
Lc50 Value ◽  
Pediatric All

Abstract Abstract 2038 Poster Board II-15 Purine nucleoside phosphorylase (PNP) deficiency in humans is associated with elevated deoxyguanosine (dGuo) plasma levels. DGuo is converted into dGTP inducing apoptosis in T-cells and this provides the rationale for the development of deoxyguanosine analogues as a potential treatment option for T-cell malignancies. Forodesine (BCX-1777; BioCryst-Mundipharma) is an efficient blocker of PNP activity, thereby boosting the conversion of dGuo into dGTP and raising intracellular dGTP levels. AraG (9-b-D-arabinofuranosyl-guanine) is a compound that is resistant to PNP-mediated degradation that is efficiently converted into AraGTP. AraGTP becomes incorporated in the DNA, blocking DNA synthesis and promoting apoptosis. In a phase II clinical trial, the AraG prodrug Nelarabine enforced a complete remission rate of 55% for pediatric T-ALL patients at 1st relapse. (Berg, JCO 2005). Clinical data of Forodesine treatment in pediatric ALL patients are not yet available. As tested on primary pediatric acute lymphoblastic leukemia (ALL) patient samples (4 T-ALL, 2 BCP-ALL), 1μM of Forodesine is sufficient to completely block PNP and abolish rapid dGuo degradation resulting in a median 7.9 (range 0.5-378) fold raise of intracellular dGTP levels. Accumulation of dGTP is comparable for T-ALL (n=31) and BCP-ALL (n=11) patient samples. This reflects equal intrinsic ability of salvage nucleotide synthesis for both T-ALL and BCP-ALL cells. Cytotoxic effect of Forodesine was tested on primary leukemia cells from newly diagnosed pediatric ALL patients in-vitro by incubating cells with Forodesine (1μM) in the presence of increasing concentrations of dGuo (0.001-50μM). In accordance with selective T-cell toxicity, T-ALL cells were more sensitive to Forodesine/dGuo treatment (median T-ALL LC50 value: 1.1μM dGuo/1μM Forodesine, n=27, p=0.001) compared to BCP-ALL cells, which had a median LC50 value of 8.8μM dGuo/1μM Forodesine (n=30). All patients that responded demonstrated dGTP accumulation (1.5-222.1 fold), although the raise of dGTP levels did not correlate with Forodesine/dGuo toxicity (r2= 0.10, p=0.22). Studying in-vitro responsiveness to AraG, T-ALL cells were more sensitive compared to BCP-ALL cells (p=0.0002) with a median AraG LC50 value of 20.5μM for T-ALL samples (n=24) versus 48.3μM for BCP-ALL samples (n=20). Remarkably, TELAML1 positive BCP-ALL cases were insensitive to AraG treatment (median LC50 value >50μM, n=9). No correlation was identified between in-vitro Forodesine/dGuo and AraG cytotoxicities (r2=0.05, p=0.29). Most patient samples that displayed AraG resistance still responded to Forodesine/dGuo treatment. This may be explained by the fact that the uptake of both drugs may be facilitated by different transporters. Using RQ-PCR we could demonstrate that AraG toxicity, in contrast to Forodesine, was significantly associated with ENT1 (equilibrative nucleoside transporter 1) expression levels (p=0.008), which was previously identified as strong predictor for AraC cytotoxicity in pediatric ALL (Stam RW. et al., Blood 2003). AraG cytotoxicity strongly correlated with AraC cytotoxicity (r2=0.71, p<0.0001). We found no significant correlation between Forodesine sensitivity and the expression levels of other nucleoside transporters (CNT1, CNT2, CNT3, ENT2), kinases (dCK, dGK), nucleotidases (NT5C1A, NT5C2, PNI) or other enzymes that are involved in dGuo metabolism (PNP, RRM1, RRM2). In conclusion, T-ALL cells are more sensitive to Forodesine/dGuo treatment in-vitro than BCP-ALL cells that have nearly 8 fold higher dGuo LC50 values. Resistance to AraG treatment does not preclude responsiveness to Forodesine treatment and vice versa, indicating that Forodesine and AraG rely on different cellular mechanisms for cytotoxicity, possibly involving differences in dependence on the nucleoside transporter ENT1. Disclosures: No relevant conflicts of interest to declare.

Targeting Survivin with YM155 As a Potential Therapy in Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2490-2490
Author(s):  
Abdusebur Jemal ◽  
Jeffrey W Tyner ◽  
Mathew Thayer ◽  
Markus Muschen ◽  
Brian J. Druker ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Ectopic Expression ◽  
Survivin Expression ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All

Abstract Abstract 2490 Background: Pediatric Acute Lymphoblastic Leukemia (ALL) remains the most common pediatric malignancy. Despite advances in treatment and outcomes, there continue to be subsets of patients that are refractory to standard intensive chemotherapy and hematopoietic stem cell transplant. Therefore, novel gene targets for therapy are needed to further advance treatment for this disease. Survivin, a member of the chromosome passenger complex and inhibitor of apoptosis has been shown to be over-expressed in malignant cells and in relapsed ALL. Therefore, survivin may be a potential target for therapy in pediatric ALL. The selective survivin suppressant, YM155 (Astellas) has been shown to inhibit survivin expression and activate cell death in multiple cell lines. Early phase I studies show promise in both tolerability and possible efficacy in B-cell malignancies. Therefore, this drug may have the potential of improving treatment for pediatric B-cell precursor ALL. Design/methods: Pediatric lymphoblastic cell lines, fresh primary lymphoblast cells from newly diagnosed patients with ALL and xenografted patient samples were used in this study. Cells were incubated in the presence of YM155 at doses ranging from 1nM to 10μM. Viability was measured using a standard methane-thiosulfonate viability assay. Activation of apoptosis was identified using the Guava nexin Annexin V binding assay for cell lines. Results: Treatment of ALL cell lines, primary patient samples and xenograft samples show a dose-dependent sensitivity to YM155 by both activation of apoptosis and by cell viability. IC50 doses for the majority of the samples are in the low nanomolar range (Table). Interestingly, there is some variability amongst patient samples suggesting possible variable responses in vivo. Ectopic expression of survivin in cell lines treated with YM155 rescues the effect of the drug. Further, t(9;22) positive ALL samples, including primary patient, xenograft, and dasatinib resistant samples remain significantly sensitive to YM155. For dasatinib sensitive Ph+ALL samples, combination therapy suggest an additive effect by isobologram analysis. Conclusion: Pediatric ALL samples remain sensitive to treatment with YM155 in cell lines, primary patient and xenografted samples. The results of these experiments will be used as a foundation to develop a comprehensive understanding of the mechanisms of survivin dependence in pediatric ALL. Future studies will also be designed to develop YM155 as an additional therapy for pediatric acute lymphoblastic leukemia. Disclosures: Druker: Cylene:; MolecularMD:; Novartis:; Bristol-Myers-Squibb:.

Crebbp HAT Domain Mutations Are Frequently Detected in Adult Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1419-1419
Author(s):  
Kenji Tokunaga ◽  
Shunichiro Yamaguchi ◽  
Eisaku Iwanaga ◽  
Tomoko Nanri ◽  
Taizo Shimomura ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Adult Patients ◽  
Prognostic Impact ◽  
Pediatric All ◽  
Crebbp Gene

Abstract Abstract 1419 Aims: Molecular pathogenesis of acute lymphoblastic leukemia (ALL) has largely been verified in pediatric patients and the identification of genetic alterations have contributed to stratifying therapeutic applications. In adult patients with ALL, cytogenetic and genetic abnormalities have not sufficiently been elucidated and therapeutic improvement has been hindered. CREB binding protein (CREBBP) is a transcriptional coactivator that interacts with a diverse range of transcription factors and regulates transcription by histone acetylation in hematopoiesis. Mutations of the CREBBP gene are recently found in approximately 2–4% of pediatric patients with ALL. Especially in relapsed cases, the mutations prevail (18–63%) and are possible markers for prediction of relapse in pediatric ALL. In adult patients with ALL, the clinical significance of CREBBP mutations remains to be determined. Here we examined adult ALL patients in an attempt to determine the incidence, clinical characteristics and prognostic impact of the CREBBP mutations. Methods: We investigated 71 adult patients with newly diagnosed ALL treated with JALSG protocols between 1986 and 2010. Age ranged from 15 to 86 years, with a median of 54 years. CREBBP mutations are dominantly identified in histone acetyltransferase (HAT) domain. HAT domain in the CREBBP gene was amplified with RT-PCR using RNA isolated from the peripheral blood or bone marrow mononuclear cells at diagnosis and was subjected to direct sequencing. We compared clinical profiles between patients with and without CREBBPHAT domain mutations. This study was approved by the Institutional Review Boards and informed consent was obtained from each patient according to guidelines based on the revised Declaration of Helsinki. Results: CREBBP HAT domain mutations were detected in 8 of 71 (11.3%) patients: one nonsense mutation, five insertion mutations with frameshifts, and five missense mutations. Two patients harbored biallelic mutations. The mutations at diagnosis in adult patients were seen more frequently than those in pediatric patients ever reported. Such mutations were not completely identical to those detected in pediatric ALL, but were seen in the region within the HAT domain, indicating that such mutations are loss-of-function mutations. The mutations were found in both B-cell (6/53: 11.3%) and T-cell (1/9: 11.1%) ALL, and distributed in patients harboring IKZF1 alterations (3/31: 9.7%) or the BCR-ABL fusion gene (2/19: 10.5%). There were no statistical difference in age, sex, leukocyte, platelet counts and complete remission rate between patients with and without the CREBBP HAT domain mutations. Patients with the mutations had a trend with worse cumulative incidence of relapse (P=0.4637), relapse-free survival (P=0.4195) and OS (P=0.2349) compared to patients lacking the mutations, but statistical significance was not detected in this small cohort. Conclusions: CREBBP HAT domain mutations at diagnosis in adult ALL are found more frequently than in pediatric ALL. This may be one of the mechanisms that adult ALL has been associated with poor OS compared with pediatric ALL. In this study, CREBBP HAT domain mutations were observed in various subtypes of ALL: both B-cell and T-cell ALL, and both Philadelphia chromosome positive and negative ALL. In pediatric ALL, CREBBP mutations were frequently seen in relapsed patients but not in previously untreated patients. These observations suggest that CREBBP mutations play an important role in an additional late event(s) leading to the development and progression of ALL. Our study implies the possibility that mutations of the CREBBP gene are associated with the pathogenesis and prognostic marker of adult ALL and represent specific epigenetic modifiers in adult ALL, serving as potential therapeutic targets. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CAR-T Cells: An Innovative Therapeutic Strategy Against Pediatric Acute Lymphoblastic Leukemia

2019 ◽  
Author(s):  
Mohsen Sheykhhasan ◽  
Hamed Manoochehri ◽  
Leila Naserpour ◽  
Naser Kalhor
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Blood Cells ◽  
Therapeutic Strategy ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Car T Cells ◽  
Car T ◽  
Negative Effect ◽  
Cancer In Children

Acute lymphoblastic leukemia (ALL) is a prevalent and highly progressive cancer in children and adolescents associated with an excessive production of immature lymphocytes in the bone marrow, which causes a negative effect on the production of other blood components, such as red blood cells, platelets, and other white blood cells (1-3).

Can Less Intensive Chemotherapy and an Autotransplant Cure Adult T-Cell Acute Lymphoblastic Leukemia?

2019 ◽  
Vol 143 (2) ◽  
pp. 131-139 ◽  
Author(s):  
Elena Parovichnikova ◽  
Vera Troitskaya ◽  
Andrey Sokolov ◽  
Olga Gavrilina ◽  
Zalina Akhmerzaeva ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Blood Cells ◽  
Lymphoblastic Leukemia ◽  
White Blood Cells ◽  
High Dose ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
Number Of Patients ◽  
Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is a rare disease usually treated with intensive, high-dose consolidation chemotherapy followed by an allotransplant in a substantial number of patients. The data of the RALL-2009 study on 125 adult T-ALL patients suggest that similar total chemotherapy doses given less intensively over a longer interval without interruptions and with an auto- rather than an allotransplant produce outcomes like current more intensive protocols and an allotransplant: 9-year cumulative incidence of relapse (CIR), leukemia-free survival (LFS), and survival were 24% (95% CI 16–33%), 70% (95% CI 59–79%) and 62% (95% CI 51–72%). In a landmark analysis, subjects achieving a complete remission and receiving an autotransplant had a lower 9-year CIR (9% [95% CI 2–22%] vs. 29% [95% CI 16–43%]; p = 0.0076) and better LFS (91% [95% CI 79–98%] vs. 58% [95% CI 41–74%]; p = 0.0009) and survival (92% [95% CI 77–99%] vs. 60% [95% CI 44–77%]; p = 0.001) compared with subjects not receiving an autotransplant. In a multivariate analysis, white blood cells ≥100 × 109/L at study entry were significantly associated with worse LFS (HR = 2.842 [95% CI 1.131–7.143]; p = 0.0263) and survival (HR = 6.085 [95% CI 1.918–19.3]; p = 0.0022) because of more early deaths (HR = 2.42 [95% CI 1.04–5.67]; p = 0.041). Receiving an autotransplant correlated with a lower CIR (HR = 0.23 [95% CI 0.07–0.73]; p = 0.0136) and better LFS (HR = 0.27 [95% CI 0.08–0.85]; p = 0.0256) and survival (HR = 0.158 [95% CI 0.045–0.550]; p = 0.0037).

In-Vitro Efficacy of the Deoxyguanoside Analogs Forodesine (BCX- 1777) and ARA-G in Pediatric Acute Lymphoblastic Leukemia Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1925-1925
Author(s):  
Irene Homminga ◽  
Christian M Zwaan ◽  
Chantal Y. Manz ◽  
Shanta Bantia ◽  
Cynthia Parker ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Nucleotide Synthesis ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Lc50 Value ◽  
Pediatric All

Abstract Purine nucleotide phosphorylase (PNP) deficiency in humans is associated with elevated dGuo plasma levels. This results in the intra-cellular conversion of dGuo into dGTP, following 3 consecutive kinase steps and depletion of T-cells resulting in immune deficiency. This T-cell toxicity provided the rationale for the development of deoxyguanosine analogues as potential therapeutic compounds for T-cell malignancies. Forodesine (BCX-1777; BioCryst-Mundipharma) is an efficient blocker of PNP activity. Forodesine facilitates the conversion of dGuo into dGTP raising the intracellular dGTP pool. AraG (9-b-D-arabinofuranosyl-guanine) is a compound that is resistant to PNP-mediated degradation resulting in phosphorylation of AraG into AraGTP. AraGTP becomes incorporated in the DNA and blocks DNA synthesis resulting in apoptosis. In a phase II clinical trial, the AraG prodrug Nelarabine enforced a complete remission rate of 55% for pediatric T-ALL patients at 1st relapse. (Berg, JCO 2005). Clinical data of forodesine treatment in pediatric ALL patients are not yet available. The cytotoxic effect of Forodesine was investigated on primary leukemia cells from newly diagnosed pediatric acute lymphoblastic leukemia (ALL) patients in-vitro. Cells were incubated with a fixed concentration of Forodesine (1μM) in the presence of increasing concentrations of dGuo (0.001–50μM). The dGTP levels under conditions where PNPactivity was completely blocked was monitored. Incubation of primary leukemic cells obtained from 6 pediatric ALL patients (4 T-ALL, 2 B-ALL) with 10μM dGuo results in rapid dGuo degradation (t½&lt;4hrs) by the PNP enzyme that is completely abolished by the addition of 1μM of Forodesine. Cells consequently accumulate dGTP levels upon Forodesine treatment to a median 7.9 (range 0.5–378 fold) that is comparable between T-ALL (n=31) and B-ALL (n=11) patient samples. This reflects equal intrinsic ability of de-novo nucleotide synthesis for both T-ALL and B-ALL cells. In accordance with T-cell selective toxicity, T-ALL cells were more sensitive to Forodesine/ dGuo treatment (median T-ALL LC50 value: 1.1μM dGuo/1μM Forodesine, n=27, p=0.001) compared to B-ALL cells, which had a median LC50 value of 8.8μM dGuo/1μM Forodesine (n=30). All patients that responded demonstrated dGTP accumulation (1.5– 222.1 fold), but the magnitude of dGTP accumulation did not relate to Forodesine/dGuo toxicity. Studying in-vitro responsiveness to AraG, T-ALL cells were more sensitive compared to B-ALL cells (p=0.0002) with a median AraG LC50 value of 20.5μM for T-ALL samples (n=24) versus 48.3μM for B-ALL samples (n=20). However, TELAML1 negative B-ALL cases were sensitive to AraG where as TELAML1 positive B-ALL cases were remarkable insensitive to AraG treatment (median LC50 value &gt;50μM, n=9). No correlation was identified between in-vitro Forodesine/dGuo and AraG cytotoxicities. Most patient samples that displayed AraG resistance still responded to Forodesine/dGuo treatment. In contrast, AraG cytotoxicity strongly correlated with AraC cytotoxicity (r2=0.71, p&lt;0.0001). In conclusion, T-ALL cells are sensitive to Forodesine/dGuo treatment in-vitro in contrast to B-ALL cells that have nearly 8 fold higher LC50 values. In-vitro Forodesine mediated cytotoxicity seems more potent in pediatric ALL than AraG treatment. Resistance to AraG treatment does not preclude responsiveness to Forodesine treatment and vice versa, indicating that Forodesine and AraG rely on different cellular mechanisms for cytotoxicity.

Higher Incidence of Treatment-Related Toxicities in Non-Hispanic Patients Undergoing Therapy for Newly Diagnosed Pediatric Acute Lymphoblastic Leukemia on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 248-248 ◽  
Author(s):  
Justine Kahn ◽  
Sergio Barrera ◽  
Randy Davila ◽  
Emily Roberts ◽  
ZheZhen Jin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Children And Adolescents ◽  
Lymphoblastic Leukemia ◽  
P Value ◽  
Newly Diagnosed ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Dana Farber Cancer Institute ◽  
Significant Difference ◽  
Hispanic Patients ◽  
Pediatric All

Abstract Background: Risk-adapted treatment strategies have contributed to excellent outcomes in pediatric acute lymphoblastic leukemia (ALL); however, treatment-associated acute and long-term toxicities persist. Therapy-associated toxicities of note in pediatric ALL are related to a treatment backbone that relies heavily on corticosteroids (prednisone and dexamethasone) and asparaginase (ASP). The most frequently observed toxicities include, but are not limited to, serious infection, pancreatitis, thrombosis and bony morbidities including osteonecrosis (ON) and fracture. Previous studies suggest that children of racial and ethnic minorities are at higher risk for treatment-associated toxicities. We assessed the incidence of treatment-related toxicities in Hispanic and non-Hispanic patients undergoing treatment for pediatric ALL. Patients and Methods: Retrospective cohort study investigating the incidence of treatment-related toxicities including infection, allergy to ASP, pancreatitis, thrombosis and bony morbidities in Hispanic and non-Hispanic children and adolescents with newly diagnosed ALL undergoing therapy on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001. The ethnicity of each patient was designated at the time of study enrollment by research coordinators. Descriptive statistics were calculated, mean +/- SD for continuous variables and frequency and percentages for categorical variables. Toxicity rates were based on number of patients. Comparison between groups was done by Chi-square test or FisherÕs exact test and p -value < 0.05 was considered significant. Results: Between 2005 and 2011, 794 children and adolescents (ages 1 - 18 years) were enrolled on Protocol 05-001, 730 of whom were evaluable for this investigation: 150 Hispanic (18%), 580 non-Hispanic (73%). Sixty-four patients did not have ethnicity documented. There was no significant difference in disease-risk group, age or gender between the two groups. Weight was significantly higher in Hispanic patients (31.9 ± 24.4 kg in Hispanic and 26.9 ± 18.7 kg in non-Hispanic, p = 0.021). There was no significant difference in the incidence of ASP-related toxicities (allergy, pancreatitis, thrombosis) between Hispanic and non-Hispanic patients. There was no significant difference in the overall incidence of infection between the two groups (42% in Hispanic and 50% in non-Hispanic, p = 0.081). Non-Hispanic patients had significantly higher rates of opportunistic infection (Pneumocystis pneumonia) than Hispanic patients (0.7% in Hispanic and 4% in non-Hispanic, p = 0.041). A similar difference in the incidence of bacteremia between the two groups approached, but did not reach statistical significance (p = 0.052). The overall incidence of fracture in all patients was 14.5% and was significantly higher in non-Hispanic patients (6% in Hispanic and 16.7% in non-Hispanic, p < 0.001). The overall incidence of ON was 8.9% and was significantly higher in non-Hispanic patients (3.3% in Hispanic and 10.3% in non-Hispanic, p = 0.007). (Table 1) Conclusion: The incidence of opportunistic infections and bony morbidities was significantly higher in non-Hispanic patients undergoing treatment for pediatric ALL on the DFCI ALL Consortium Protocol 05-001. The risk for, and impact of therapy-related toxicities varies by a patientÕs treatment tolerance, perhaps as a function of age and gender or as a result of disease biology or genetic polymorphisms affecting drug metabolism. Additionally, non-biologic factors such as medication adherence and nutritional status may also contribute to toxicity incidence in patients undergoing treatment for pediatric ALL. Prospective studies to further investigate our findings are warranted. Table. All Patients, (N = 730) Non-Hispanic, (N = 580) Hispanic, (N = 150) p -value Overall Infection 353/730 (48.4%) 290/580 (50%) 63/150 (42%) 0.081 Bacteremia 289/730 (39.6%) 240/580 (41.4%) 49/150 (9.3%) 0.052 Opportunistic Infection 24/730 (3.3%) 23/580 (4%) 1/150 (0.7%) 0.041 Fracture 106/730 (14.5%) 97/580 (16.7%) 9/150 (6%) <0.001 Osteonecrosis 65/730 (8.9%) 60/580 (10.3%) 5/150 (3.3%) 0.007 Thrombosis* 36/730 (4.9%) 26/580 (4.5%) 10/150 (6.7%) 0.271 Pancreatitis* 78/730 (10.7%) 60/580 (10.3%) 18/150 (12%) 0.559 ASP Allergy* 76/730 (10.4%) 57/580 (9.8%) 19/150 (12.7%) 0.310 *ASP-related toxicity Disclosures No relevant conflicts of interest to declare.

Pcft Is Silenced By DNA Methylation In Pediatric Acute Lymphoblastic Leukemia Resulting In Decreased Methotrexate Uptake

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3768-3768
Author(s):  
Calvin K. Lee ◽  
Weijie Poh ◽  
Megan Healey ◽  
Eric S Schafer ◽  
Patrick Brown ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Cell Lines ◽  
Promoter Methylation ◽  
Lymphoblastic Leukemia ◽  
Qrt Pcr ◽  
Hypomethylating Agent ◽  
Pediatric All

Abstract Introduction Acute lymphoblastic leukemia (ALL) remains the most common cancer diagnosis in children, accounting for 21% of all pediatric cancers from birth to 19 years. Antifolate therapy, specifically treatment with methotrexate, is central in ALL therapy. Genetic polymorphisms, such as those for MTHFR and SLC01B1 can contribute to how methotrexate is metabolized and can alter side effect profiles, but they do not fully explain why transformed cells may become resistant to methotrexate. Epigenetic abnormalities, including dysregulation of DNA methylation, is frequent in all types of cancers including ALL, often leading to silencing of tumor suppressor genes. Epigenetic silencing could potentially influence a cell's sensitivity to antifolate therapy. PCFT is a low pH folate transporter and the regulation of PCFT gene expression includes DNA methylation. Previous studies have demonstrated that treatment with a hypomethylating agent results in reexpression of the gene. PCFT methylation, however, has not yet been studied in primary cancer tissues. Decreased or absent levels of PCFT could result in decreased methotrexate uptake and provide a mechanism of resistance. Methods Genomic DNA and RNA were isolated from primary pediatric ALL samples as well as ALL cell lines. Methylation status was evaluated using methylation specific PCR (MSP). Expression was measured using qRT-PCR. Cell lines were treated with the hypomethylating agent 5-Aza-2-deoxycytidine (5-Aza-2dC). After treatment with 5-Aza-2dC, RNA was isolated for expression. Cells were also evaluated for methotrexate entry into the cell using fluorescein-tagged methotrexate. Results We found that 100% of ALL cell lines (n=5) were methylated at PCFT. In primary patient samples, among an initial cohort, 23/33 samples (70%) had methylation at PCFT by MSP. By subtype of ALL, methylation of PCFT was found in 14/21 (67%) of B-cell ALL and 9/12 (75%) of T-cell ALL. This cohort did not have RNA available or outcome data. In a second pediatric ALL cohort of newly diagnosed patients, 23/40 (57%) were methylated at the PCFT promoter. Among these samples, 19/33 B-cell ALL, and 4/7 T-cell ALL were methylated at PCFT. The mean diagnostic age of the patients with PCFT promoter methylation was lower (7.13 years) than those that were unmethylated (8.71 years). Within this cohort with between 4.5 and 15 years of time elapsed since diagnosis, only 3 patients experienced recurrent or refractory disease. Of these patients, 1 had methylation of PCFT. Expression analysis by qRT-PCR demonstrated that 2 cell lines had no expression of PCFT (Tanoue and Nalm6) while 1 cell line expressed low level PCFT despite having promoter methylation (HB 11;19). Among the primary ALL samples, the unmethylated group had a higher mean expression of PCFT (1/ΔCt = 0.068) than the methylated group (1/ΔCt = 0.0635; p=0.045), suggesting that methylation of PCFT leads to decreased expression. Treatment of the ALL cell lines with 5-Aza-2dC did induces expression of PCFT in Nalm6 and Tanoue, but did not increase expression in HB 11;19 where expression was already present. After treatment with 5-Aza-2dC, Nalm6 and Tanoue also increased the intake of methotrexate by 2.25 and 1.7 times respectively, while in HB 11;19, the methotrexate intake decreased by a factor of 0.73. Conclusions PCFT is frequently methylated in both B-cell and T-cell pediatric ALL. DNA methylation was associated with decreased expression in primary samples. Hypomethylating agents can reverse this gene silencing resulting in higher methotrexate entry into the cell, providing a potential strategy for overcoming methotrexate resistance. Disclosures: No relevant conflicts of interest to declare.

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