Changes in the concentration of vitamin D in the course of intensive treatment of acute lymphoblastic leukemia. A preliminary data

2015 ◽  
Author(s):  
Katarzyna Muszynska-Roslan ◽  
Eryk Latoch ◽  
Anna Panasiuk ◽  
Malgorzata Sawicka-Zukowska ◽  
Maryna Krawczuk-Rybak
Keyword(s):  
Vitamin D ◽  
Acute Lymphoblastic Leukemia ◽  
Preliminary Data ◽  
Lymphoblastic Leukemia ◽  
Intensive Treatment

scholarly journals Translocation (9;22) is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 435-439 ◽  
Author(s):  
JA Fletcher ◽  
EA Lynch ◽  
VM Kimball ◽  
M Donnelly ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Intensive Treatment ◽  
First Remission ◽  
Prognostic Implications

Abstract The prognostic implications of t(9;22)(q34;q11) were assessed at a median follow-up of 3.5 years in 434 children receiving intensive treatment for acute lymphoblastic leukemia (ALL). Four-year event-free and overall survivals were 81% and 88%, respectively, in 419 children lacking t(9;22), but were 0% and 20%, respectively, in 15 children with t(9;22) (P less than .001). Poor outcome for children with t(9;22)- positive ALL was particularly notable because we have reported improved survival in other historically poor prognosis ALL cytogenetic categories when treated with similarly intensive therapy. We recommend that very intensive treatment approaches, including bone marrow transplantation in first remission, be considered for all children with t(9;22)-positive ALL.

Tubacin, An Inhibitor of HDAC6, Induces Apoptosis of Acute Lymphoblastic Leukemia Cells in Vitro and in Vivo through a Na+/K+ATPase-Dependent Pathway.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1923-1923 ◽  
Author(s):  
Agustin Rodriguez-Gonzalez ◽  
Tiffany Simms-Waldrip ◽  
Alan K. Ikeda ◽  
Tara Lin ◽  
Brett Lomenick ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
Preliminary Data ◽  
Lymphoblastic Leukemia ◽  
Parp Cleavage ◽  
Sodium Glutamate ◽  
Alpha Tubulin ◽  
Acetylated Tubulin ◽  
Treat All

Abstract Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. Despite effective chemotherapy, 25 to 30% of children will relapse. In adults, less than 30% of patients with ALL are cured. Therefore, it is critical that we identify novel therapies to treat ALL. We are studying the effects of a small molecule compound known as tubacin (tubulin acetylation inducer) that selectively inhibits histone deacetylase 6 (HDAC6) resulting in increased acetylation of alpha-tubulin by inhibiting one of the two catalytic domains of HDAC6. We found that treatment of both pre-B and T-ALL cell lines with tubacin inhibits growth at very low micromolar concentrations (Jurkat IC50=1μM, Loucy IC50=3μM, REH IC50=2μM, Nalm6 IC50=5μM). We also determined that there is a therapeutic window, since tubacin inhibits the growth of normal bone marrow progenitor cells in methylcellulose colony assays at 20μM and normal human lymphocytes cultured in IL-2 at an IC50 of 16μM. We next tested the effects of tubacin in vivo. SCID mice injected with pre-B ALL Nalm-6 cells were treated with tubacin intraperitoneally at 50 mg/kg/day. Preliminary data using bioluminescence imaging in SCID mouse models showed that tubacin inhibited leukemic progression in vivo. To understand the mechanism of tubacin in ALL cells, we examined both apoptosis and cell cycle regulation by PARP cleavage, activation of caspases, and propidium iodide staining with FACs analysis. Tubacin induced apoptosis of pre-B and T-ALL cells within 12 hours of treatment. There was no effect on cell cycle progression, Retinoblastoma protein phosphorylation, or p21 upregulation, which have been observed with other HDAC inhibitors. Unlike in myeloma cells, tubacin did not increase JunK/SAPK activation or accumulation of acetylated HSP90 in ALL cells. Tubacin treatment resulted in accumulation of acetylated alpha-tubulin after 1 hour and an increase in polyubiquitinated proteins after 7 hours. To address potential mechanisms of tubacin in ALL, we tested whether Na+/K+ ATPase could be contributing to apoptosis. Previous work has shown that treatment with L-glutamate dissociates the Na+/K+ ATPase complex from acetylated tubulin and restores ATPase enzymatic activity. We hypothesized that the accumulation of acetylated tubulin could potentially inhibit the activity of the cytosolic Na/K ATPase pump, which could be reversed by treatment with 1mM sodium glutamate. Preliminary data demonstrate that we can partially rescue the effects of tubacin on PARP cleavage with sodium glutamate. These results suggest that tubacin induces apoptosis through a novel pathway in ALL cells and provide rationale for targeting the aggresome pathway to treat ALL in the future.

Low CNS Relapse Incidence without Radiotherapy and Improvement of Outcome: Results of Subsequent EORTC-CLG 58881 and 58951 Trials in Pediatric T-Cell Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 133-133 ◽  
Author(s):  
Barbara De Moerloose ◽  
Stefan Suciu ◽  
Alina Ferster ◽  
Françoise Mazingue ◽  
Nicolas Sirvent ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Intensive Treatment ◽  
Phase Iii ◽  
Average Risk ◽  
Long Term Outcome ◽  
Cns Relapse ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Abstract 133 Background: T-cell acute lymphoblastic leukemia (ALL) accounts for 15% of ALL cases in children and has been associated with a higher risk for central nervous system (CNS) relapse and a worse prognosis. In EORTC trials 58831 and 2, standard risk (SR) patients (pts) were not irradiated but received intermediate dose methotrexate (MTX) courses; for medium and high risk pts, high dose (HD) MTX was added to the treatment regimen and the administration of cranial radiotherapy (RT) was randomised. The omission of RT didn't result in an increase of CNS or systemic relapse and consequently, CNS-directed chemotherapy was substituted for RT in all following trials. The long-term outcome of T-ALL pts in the subsequent phase III trials (58881 and 58951) are presented here. Methods: The BFM backbone for ALL treatment was applied to all EORTC-CLG trials since 1983. As CNS treatment in study 58881, SR pts received 4 HD MTX courses (5 g/m2) in interval therapy and 10 IT MTX injections during the intensive treatment phases. Pts with CNS-3 status at diagnosis received 2 additional IT injections during induction, 2 during consolidation and 6 HD MTX courses + IT during maintenance. T-ALL pts with poor prephase response (PPR) at day 8 or who didn't achieve complete remission (CR) after induction were included in the very high risk (VHR) group. VHR CNS-directed chemotherapy included 10 IT MTX injections, 6 IT triple and 10 HD MTX courses during intensive treatment phases, followed by 4 IT MTX injections during maintenance (the latter for CNS-3 pts only). In the 58951 trial, all T-ALL pts had an intensified induction. The CNS-directed therapy of all average risk T-ALL pts was intensified to 11 HD MTX courses, 1 IT with MTX and 15 triple IT. MRD ≥ 1% at the end of induction was added as VHR criterium. All non-transplanted VHR pts received 1 IT MTX injection, 19 IT triple and 9 HD MTX courses. Several randomized questions were addressed in both trials of which most relevant for T-ALL pts: in study 58881 the comparison E.coli asparaginase (ASP) Medac versus (vs) “other ASP” (= Erwinia ASP or E.coli ASP Bayer); in trial 58951 1) the comparison dexamethasone (DEX 6 mg/m2/d) vs prednisolone (PRED 60 mg/m2/d) in induction and 2) conventional vs prolonged E.coli ASP for non-VHR pts. Results: 303 and 296 T-ALL pts were included in trials 58881 and 58951 resp, representing 14.5% and 15.2% of all pts. Outcome results and type of events for the entire 58881 and 58951 cohorts and according to several subgroups are presented in the table. The 8-year isolated and overall CNS relapse incidences were 6.8% and 10.9% in study 58881, 5.3% and 8.5% in study 58951. The 8-year EFS, DFS and OS improved remarkably in study 58951. In the latter trial, outcome improvement was particularly seen in pts with initial WBC<100x10E9/L and in the good prephase responders (GPR) which had a significant better outcome than those with PPR. 58881 pts assigned to the “other ASP” arm had an inferior outcome. Concerning the DEX/PRED comparison in the 58951 T-ALL cohort, no advantage was seen for EFS (hazard ratio (HR) (99%CI): 1.26 (0.70;2.27)) or OS. There even was a trend towards worse EFS for pts with initial WBC>100x10E9/L and for pts with PPR treated in the DEX arm (HR (99%CI): 1.52 (0.63;3.64) and 1.47 (0.64;3.35)). Prolonged ASP treatment did not improve outcome of the whole T-ALL 58951 cohort. Conclusion: Prophylactic and therapeutic RT can safely be omitted from frontline treatment of children with T-ALL. Adequate ASP therapy, intensified induction treatment and CNS directed therapy can result in a significant improvement of the outcome of at least 2/3rd of T-ALL pts, particularly those with initial WBC<100x10E9/L and GPR. Disclosures: No relevant conflicts of interest to declare.

Effect of 1,25(OH)2—Vitamin D on Bone Mass in Children With Acute Lymphoblastic Leukemia

2008 ◽  
Vol 30 (1) ◽  
pp. 15-19 ◽  
Author(s):  
Paulina R. Díaz ◽  
Laura C. Neira ◽  
Sylvia G. Fischer ◽  
María C. Teresa Torres ◽  
Aída T. Milinarsky ◽  
...  
Keyword(s):  
Vitamin D ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Mass ◽  
Lymphoblastic Leukemia

scholarly journals Translocation (9;22) is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 435-439
Author(s):  
JA Fletcher ◽  
EA Lynch ◽  
VM Kimball ◽  
M Donnelly ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Intensive Treatment ◽  
First Remission ◽  
Prognostic Implications

The prognostic implications of t(9;22)(q34;q11) were assessed at a median follow-up of 3.5 years in 434 children receiving intensive treatment for acute lymphoblastic leukemia (ALL). Four-year event-free and overall survivals were 81% and 88%, respectively, in 419 children lacking t(9;22), but were 0% and 20%, respectively, in 15 children with t(9;22) (P less than .001). Poor outcome for children with t(9;22)- positive ALL was particularly notable because we have reported improved survival in other historically poor prognosis ALL cytogenetic categories when treated with similarly intensive therapy. We recommend that very intensive treatment approaches, including bone marrow transplantation in first remission, be considered for all children with t(9;22)-positive ALL.

Cardiovascular dysfunction and vitamin D status in childhood acute lymphoblastic leukemia survivors

2019 ◽  
Vol 15 (5) ◽  
pp. 465-470 ◽  
Author(s):  
Paola Muggeo ◽  
Vito Michele Rosario Muggeo ◽  
Paola Giordano ◽  
Maurizio Delvecchio ◽  
Maria Altomare ◽  
...  
Keyword(s):  
Vitamin D ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Vitamin D Status ◽  
Cardiovascular Dysfunction
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