scholarly journals In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3861-3868 ◽  
Author(s):  
E Klumper ◽  
R Pieters ◽  
AJ Veerman ◽  
DR Huismans ◽  
AH Loonen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Poor Prognosis ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Childhood All ◽  
Acquired Drug Resistance ◽  
The Poor ◽  
Response To Chemotherapy

Cellular drug resistance is thought to be an important cause of the poor prognosis for children with relapsed or refractory acute lymphoblastic leukemia (ALL), but it is unknown when, to which drugs, and to what extent resistance is present. We determined in vitro resistance to 13 drugs with the MTT assay. Compared with 141 children with initial ALL, cells from 137 children with relapsed ALL were significantly more resistant to glucocorticoids, L-asparaginase, anthracyclines, and thiopurines, but not to vinca-alkaloids, cytarabine, ifosfamide, and epipodophyllotoxins. Relapsed ALL cells expressed the highest level of resistance to glucocorticoids, with a median level 357- and >24-fold more resistant to prednisolone and dexamethasone, respectively, than initial ALL cells, whereas the resistance ratios for the other drugs differed from 0.8- to 1.9-fold, intraindividual comparisons between initial and relapsed samples from 16 children with ALL showed that both de novo and acquired drug resistance were involved. Specific in vitro drug-resistance profiles were associated with high-risk relapsed ALL groups. In vitro drug resistance was also related to the clinical response to chemotherapy in relapsed/refractory childhood ALL. We conclude that drug resistance may explain the poor prognosis for children with relapsed/refractory ALL. These day may be helpful to design alternative treatment regimens for relapsed childhood ALL.

Sensitivity of Childhood Acute Lymphoblastic Leukemia (ALL) to Idarubicin Is Significantly Higher Than to Daunorubicin Treatment Based on Ex Vivo Apoptosis Induction.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4495-4495
Author(s):  
Aram Prokop ◽  
Banu Bagci ◽  
Guenaelle Lingfeld ◽  
Lucia Badiali ◽  
Karin Garbrecht ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Response Rate ◽  
De Novo ◽  
Ex Vivo ◽  
Lymphoblastic Leukemia ◽  
Cell Populations ◽  
Apoptosis Induction ◽  
Good Tolerability ◽  
Childhood All

Abstract Anthracyclines, especially daunorubicin, play a very important role in the treatment of acute lymphoblastic leukemia (ALL) and the relapsed ALL in childhood. In the present study, primary lymphoblasts isolated from 65 children with de novo ALL (median: 5.8 years; range: 1.9 – 16.9 years) and relapsed ALL (median: 12.7 years; range: 1.3 – 17.9 years) were treated with daunorubicin (10 mmol/l) or idarubicin (2 mmol/l) in vitro. We could show that both anthracylines induce apoptosis, as evidenced by measurement of genomic DNA fragmentation. Interestingly, daunorubicin only induced modest apoptosis, whereas idarubicin displayed a significantly stronger apoptosis inducing effect. Furthermore the treatment of daunorubicin-resistant lymphoblasts with idarubicin resulted in good response in most of the resistant cell populations. Out of the 65 patients analysed in this study 23 were female (13 de novo ALL, 10 relapsed ALL) and 42 were male (29 de novo ALL, 13 relapsed ALL). Primary lymphoblasts were obtained by bone marrow aspiration and separated by centrifugation over Ficoll. Within these cell populations following immunologic subgroups were found: 35 c-ALL, 10 pre-B-ALL, 7 pro-B-ALL, 10 T-ALL and 3 pre-T-ALL. Daunorubicin induced apoptosis in 33 out of 65 lymphoblast populations (response rate 50.8 %). Nevertheless, a far higher response rate was observed for idarubicin with 59/65 (90,8 %) (p < 0.008), if response is defined as apoptosis induction higher than 1 %. Daunorubicin-resistance was found in 32/65 (49,2 %), resistance to both was observed in 6/65 (9,2 %). Treatment of daunorubicin-resistant lymphoblasts with idarubicin resulted in significant apoptosis induction in 26 out of 32 cell populations (81,3 %). We clearly demonstrated here that the in vitro treatment of lymphoblasts from children with de novo or relapsed ALL with idarubicin induces significantly higher response rates than daunorubicin treatment. The ex vivo sensitivity of daunorubicin-resistant lymphoblasts of childhood ALL to idarubicin treatment reflects the better potency of idarubicin to induce apoptosis and to overcome daunorubicin resistance. These data prompted us to study the clinical relevance of idarubicin in ongoing clinical trials to improve existing therapeutic regiments. First clinical data point to a good tolerability of idarubicin in the treatment of relapsed ALL in childhood.

scholarly journals In Vitro Drug Sensitivity Testing Can Predict Induction Failure and Early Relapse of Childhood Acute Lymphoblastic Leukemia

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2959-2965 ◽  
Author(s):  
Teruaki Hongo ◽  
Shuhei Yajima ◽  
Minoru Sakurai ◽  
Yasuo Horikoshi ◽  
Ryoji Hanada
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Drug Sensitivity ◽  
Lymphoblastic Leukemia ◽  
Sensitivity Testing ◽  
Childhood All ◽  
Drug Sensitivity Testing ◽  
Induction Failure ◽  
Sensitive Group

Abstract It is vital to develop effective therapy for children with acute lymphoblastic leukemia (ALL), in whom no remission occurs or who suffer relapse with current protocols. Cellular drug resistance is thought to be an important cause of induction failure and relapse. We performed in vitro tests of bone marrow samples in 196 children with newly diagnosed ALL with a 4-day culture and a methyl-thiazol-tetrazolium assay. We tested 16 drugs and calculated the 70% lethal dose (LD70) for 14 drugs and the leukemic cell survival (LCS) rate for dexamethasone and prednisolone. For each single drug, patients were classified into two groups, sensitive or resistant, by median concentration of LD70 or LCS. When patients were classified into three groups by sensitivity to four drugs of DPAV (dexamethasone, prednisolone, L-asparaginase, and vincristine), 3-year event-free survival (EFS; 95% confidence intervals) of the super sensitive group (SS; sensitive to all 4 drugs) was 0.833 (0.690 to 0.976), that of the intermediate sensitive group (IS; sensitive to 2 or 3 drugs) was 0.735 (0.609 to 0.863), and that of the relatively resistant group (RR; sensitive to no drugs or to 1 drug) was 0.541 (0.411 to 0.670; P = .0008). We then investigated the relationship between the above four-drug sensitivity and the time of relapse. The SS and IS patients tended to maintain continuous complete remission, and RR patients tended to undergo induction failure and early and late relapse (P = .004). Initial white blood cell count, immunologic classification, and age were also predictive factors, but the patient numbers showed no statistical correlation between these factors and the four-drug sensitivity groups (SS, IS, and RR). When we took three groups SS/IS/RR and investigated the EFS for various clinical groups, DPAV sensitivity strongly influenced EFS in the standard-risk ALL (P = .016). In vitro drug sensitivity testing provides additional prognostic information about childhood ALL, and early detection of drug resistance at the time chemotherapy commences may provide a successful strategy for individualizing treatment, as the results indicate de novo resistance to front-line drugs and suggest alternative, second-line drugs.

scholarly journals In Vitro Cellular Drug Resistance and Prognosis in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2723-2729 ◽  
Author(s):  
G.J.L. Kaspers ◽  
A.J.P. Veerman ◽  
R. Pieters ◽  
C.H. Van Zantwijk ◽  
L.A. Smets ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Clinical Response ◽  
Mtt Assay ◽  
Combination Chemotherapy ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Response To Chemotherapy

Abstract As an important determinant of the response to chemotherapy, measurements of cellular drug resistance may provide prognostically significant information, which could be useful for optimal risk-group stratification. The objective of this report is to determine the relation between in vitro resistance to 12 drugs, measured with the colorimetric methyl-thiazol-tetrazolium (MTT) assay, and long-term clinical response to chemotherapy in 152 children with newly diagnosed acute lymphoblastic leukemia. At risk-group stratified analyses, in vitro resistance to prednisolone, L-asparaginase, and vincristine were each significantly (P < .01) related to the probability of disease-free survival (pDFS) after combination chemotherapy. The combination of data for prednisolone, L-asparaginase, and vincristine provided a drug-resistance profile with prognostic independent significance superior to that of any single drug or any other factor. The 3-years pDFS was 100% for the group with the most sensitive profile, 20% of all patients, 84% (SE 6%) for the group with an intermediately sensitive profile, 40% of all patients, and 43% (SE 8%) for the remaining group with the most resistant profile (P < .001). In conclusion, the extent of in vitro cellular resistance to prednisolone, L-asparaginase, and vincristine, measured using the MTT assay, was significantly related to the clinical response to combination chemotherapy. Treatment failure in newly diagnosed childhood ALL can be predicted based on cellular drug resistance data.

scholarly journals In Vitro Cellular Drug Resistance and Prognosis in Newly Diagnosed Childhood Acute Lymphoblastic Leukemia

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2723-2729 ◽  
Author(s):  
G.J.L. Kaspers ◽  
A.J.P. Veerman ◽  
R. Pieters ◽  
C.H. Van Zantwijk ◽  
L.A. Smets ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Clinical Response ◽  
Mtt Assay ◽  
Combination Chemotherapy ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Response To Chemotherapy

As an important determinant of the response to chemotherapy, measurements of cellular drug resistance may provide prognostically significant information, which could be useful for optimal risk-group stratification. The objective of this report is to determine the relation between in vitro resistance to 12 drugs, measured with the colorimetric methyl-thiazol-tetrazolium (MTT) assay, and long-term clinical response to chemotherapy in 152 children with newly diagnosed acute lymphoblastic leukemia. At risk-group stratified analyses, in vitro resistance to prednisolone, L-asparaginase, and vincristine were each significantly (P < .01) related to the probability of disease-free survival (pDFS) after combination chemotherapy. The combination of data for prednisolone, L-asparaginase, and vincristine provided a drug-resistance profile with prognostic independent significance superior to that of any single drug or any other factor. The 3-years pDFS was 100% for the group with the most sensitive profile, 20% of all patients, 84% (SE 6%) for the group with an intermediately sensitive profile, 40% of all patients, and 43% (SE 8%) for the remaining group with the most resistant profile (P < .001). In conclusion, the extent of in vitro cellular resistance to prednisolone, L-asparaginase, and vincristine, measured using the MTT assay, was significantly related to the clinical response to combination chemotherapy. Treatment failure in newly diagnosed childhood ALL can be predicted based on cellular drug resistance data.

Prednisolone Resistance in Childhood Acute Lymphoblastic Leukemia: Vitro-Vivo Correlations and Cross-Resistance to Other Drugs

Blood ◽  
1998 ◽  
Vol 92 (1) ◽  
pp. 259-266 ◽  
Author(s):  
G.J.L. Kaspers ◽  
R. Pieters ◽  
C.H. Van Zantwijk ◽  
E.R. VanWering ◽  
A. Van Der Does-Van Den Berg ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Clinical Outcome ◽  
Clinical Response ◽  
Lymphoblastic Leukemia ◽  
Cross Resistance ◽  
Short Term ◽  
Childhood All ◽  
Response To Chemotherapy

As an important determinant of response to chemotherapy, accurate measurement of cellular drug resistance may provide clinically relevant information. Our objectives in this study were to determine the relationship between in vitro resistance to prednisolone (PRD) measured with the colorimetric methyl-thiazol-tetrazolium (MTT) assay, and (1) short-term clinical response to systemic PRD monotherapy, (2) long-term clinical outcome after combination chemotherapy within all patients and within the subgroups of clinical good and poor responders to PRD, and (3) in vitro resistance to 12 other drugs in 166 children with newly diagnosed acute lymphoblastic leukemia (ALL). The 12 clinical poor PRD responders had ALL cells that were median 88-fold more in vitro resistant to PRD than 131 good responders (P = .013). Within all patients, increased in vitro resistance to PRD predicted a significantly worse long-term clinical outcome, at analyses with and without stratification for clinical PRD response, and at multivariate analysis (P ≤ .001). Within both the clinical good and poor responder subgroups, increased in vitro resistance to PRD was associated with a worse outcome, which was significant within the group of clinical good responders (P &lt; .001). LC50 values, ie, lethal concentrations to 50% of ALL cells, for PRD and each other drug correlated significantly with those of all other 12 drugs, with an average correlation coefficient of 0.44 (standard deviation 0.05). The highest correlations were found between structurally related drugs. In conclusion, in vitro resistance to PRD was significantly related to the short-term and long-term clinical response to chemotherapy, the latter also within the subgroup of clinical good responders to PRD. There was a more general in vitro cross-resistance between anticancer drugs in childhood ALL, although drug-specific activities were recognized.

scholarly journals In vitro drug-resistance profile in infant acute lymphoblastic leukemia in relation to age, MLL rearrangements and immunophenotype

Leukemia ◽  
2004 ◽  
Vol 18 (3) ◽  
pp. 521-529 ◽  
Author(s):  
N L Ramakers-van Woerden ◽  
H B Beverloo ◽  
A J P Veerman ◽  
B M Camitta ◽  
A H Loonen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Resistance Profile ◽  
Drug Resistance Profile ◽  
Infant Acute Lymphoblastic Leukemia

scholarly journals TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4252-4258 ◽  
Author(s):  
TW McLean ◽  
S Ringold ◽  
D Neuberg ◽  
K Stegmaier ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All ◽  
Polymerase Chain ◽  
B Lineage

Abstract Polymerase chain reaction-based screening of childhood acute lymphoblastic leukemia (ALL) samples showed that a TEL/AML1 fusion transcript was detected in 27% of all cases, representing the most common known gene rearrangement in childhood cancer. The TEL/AML1 fusion results from a t(12;21)(p13;q22) chromosomal translocation, but was undetectable at the routine cytogenetic level. TEL/AML1-positive patients had exclusively B-lineage ALL, and most patients were between the ages of 2 and 9 years at diagnosis. Only 3/89 (3.4%) adult ALL patients were TEL/AML1-positive. Most importantly, TEL/AML1-positive children had a significantly lower rate of relapse compared with TEL/AML1-negative patients (0/22 v 16/54, P = .004). Co- immunoprecipitation experiments demonstrated that TEL/AML-1 formed homodimers in vitro, and heterodimerized with the normal TEL protein when the two proteins were expressed together. The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.

scholarly journals Poor prognosis of children with pre-B acute lymphoblastic leukemia is associated with the t(1;19)(q23;p13): a Pediatric Oncology Group study

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 117-122 ◽  
Author(s):  
WM Crist ◽  
AJ Carroll ◽  
JJ Shuster ◽  
FG Behm ◽  
M Whitehead ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Lymphoblastic Leukemia ◽  
Pediatric Oncology ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocations ◽  
Oncology Group ◽  
Childhood All ◽  
Pediatric Oncology Group ◽  
Worse Prognosis

Abstract The prognostic significance of chromosomal translocations, particularly t(1;19) (q23;p13), was evaluated in children with pre-B and early pre-B acute lymphoblastic leukemia (ALL). Patients were treated on a risk- based protocol of the Pediatric Oncology Group (POG) between February 1986 and May 1989. An abnormal clone was detected in 46% (130 of 285) of pre-B cases and 56% (380 of 679) of early pre-B cases. Translocation of any type was associated with a worse treatment outcome than other karyotypic abnormalities: 15 of 66 versus 3 of 64 failed therapy in the pre-B group (P = .001), and 37 of 141 versus 23 of 239 failed in the early pre-B group (P less than .001). The t(1;19) (q23;p13) occurred significantly more often in cases of pre-B ALL with a clonal abnormality than in early pre-B ALL cases (29 of 130 v 5 of 380, P less than .001). Among the 285 pre-B cases in which bone marrow was studied cytogenetically, those with t(1;19) had a significantly worse treatment outcome than all others (11 of 29 v 27 of 256 have failed therapy, P less than .001). This difference is significant (P less than .001) after adjustment for leukocyte count, age, and other relevant features. Cases with the t(1;19) also had a worse prognosis than pre-B patients with other translocations (4 of 37 have failed, P less than .01) or with any other karyotypic abnormality (7 of 101 have failed, P less than .001). We conclude that chromosomal translocations confer a worse prognosis for non-T, non-B-cell childhood ALL, and that the t(1;19) is largely responsible for the poor prognosis of the pre-B subgroup.

scholarly journals AVA4746, an Orally Available, Clinical Grade Antagonist of Integrin Alpha 4, Sensitizes Pre-B Cell Acute Lymphoblastic Leukemia to Chemotherapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2765-2765 ◽  
Author(s):  
Yongsheng Ruan ◽  
Eun Ji Gang ◽  
Hye-Na Kim ◽  
Chintan Parekh ◽  
Hisham Abdel-Azim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Metabolic Activity ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Drug Resistant ◽  
Support Research

Abstract Background. Even though remarkable progress has been made in the treatment of childhood acute lymphoblastic leukemia (ALL), salvage of relapse patients remains a challenge. The role of the bone marrow (BM) microenvironment is critical to protect leukemia cells from chemotherapy. The BM microenvironment promotes cell adhesion-mediated drug resistance (CAM-DR) in ALL.We and others have shown that the adhesion molecule integrin α4, referred to hereafter as α4, mediates drug resistance of B-ALL. In our previous studies, we showed that both α4 blockade by natalizumab and inhibition by the small molecule α4 antagonist TBC3486 can sensitize relapsed ALL cells to chemotherapy. However, no α4 targeting therapy is currently clinically available to treat leukemia. Here, we preclinically evaluate a novel non-peptidic small molecule antagonist, AVA4746, which has been safely used in clinical studies, as a potential new approach to combat drug resistant ALL. Method. Six refractory or relapsed primary pre-B ALL cases were used for in vitro studies. Viability was assessed by trypan blue counts or annexin V/7AAD flow cytometric analysis and metabolic activity was evaluated by Cytoscan WST-1 assay. For in vivo evaluation a NOD/SCID IL2Rγ-/- xenograft model of primary pre-B ALL (LAX7R) was used.AVA4746 (15mg/kg) was administered by oral gavage twice a day continuously for 14 days, and vincristine, dexamethasone, L-asparaginase (VDL) was given intraperitoneally (weekly) for 4 weeks. Overall survival was determined by Kaplan-Meier Survival analysis. Results. AVA4746 caused a significant decrease in mean fluorescence intensity (MFI) of α4 expression in six out of six ALL cases at doses of both 5μM and 25μM after 24 hours and 96 hours compared to DMSO control. Interestingly, decreased protein expression of α4 was also observed by Western Blot analysis all six ALL cases. We tested next in two cases (LAX53, ICN13), if AVA4746 de-adheres ALL cells from its counter receptor VCAM-1. The percentages of adherence after treatment with AVA4746 (25μM) were significantly lower than after DMSO treatment (10.3%±4.9% vs. 99.9%±7.6%, p= 0.00007 for LAX7R; 8.1%±1.0% vs. 100.1%±13.6%, p= 0.0003 for LAX53; 9.0%±1.6% vs. 100.0%±14.0%, p=0.0004 for ICN13). AVA4746 was not associated with apoptosis in vitro alone or in combination with chemotherapy (VDL). Metabolic activity as assessed by WST-1 assay was markedly decreased by AVA4746 in two of two ALL cases. AVA4746 also decreased ALL proliferation in two out of two ALL samples tested. In vivo, AVA4746 in combination with VDL chemotherapy treatment led to significant prolongation of overall survival (n=6) compared with the VDL only treated group (n=6) (MST= 78.5 days vs MST= 68 days; P<0.05). There was no significant difference in survival between the PBS control group (n=5) and the AVA4746 mono-treatment group (n=5) (MST=38days vs MST= 38days). Conclusion. We have identified α4 as a central adhesion molecule in CAM-DR of ALL and have shown that AVA-4746, an orally available and specific α4 antagonist, which has been safely used in clinical studies, downregulates α4 in primary ALL and functionally de-adheres them from VCAM-1. Critically, we demonstrated that inhibition of α4 in combination with standard chemotherapy can prolong the survival of NSG mice bearing pre-B ALL. These data support further study of inhibition of α4 using AVA4746 as a novel strategy to treat drug resistant B lineage ALL. Disclosures Bhojwani: Amgen: Other: Blinatumumab global pediatric advisory board 2015. Wayne:Spectrum Pharmaceuticals: Honoraria, Other: Travel Support, Research Funding; Kite Pharma: Honoraria, Other: Travel support, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel Support; Medimmune: Honoraria, Other: Travel Support, Research Funding; NIH: Patents & Royalties. Kim:Antisense Therapeutics Ltd: Patents & Royalties.

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