scholarly journals Methotrexate-Associated Toxicity in Children with Down Syndrome and Acute Lymphoblastic Leukemia during Consolidation Therapy with High Dose Methotrexate According to ALL-BFM Treatment Regimen

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1378-1378 ◽  
Author(s):  
Mirko Kroll ◽  
Kirsten Bleckmann ◽  
Anja Möricke ◽  
Denis Martin Schewe ◽  
Martin Stanulla ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Plasma Levels ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Severe Toxicity ◽  
Toxicity Data ◽  
Children With Down Syndrome ◽  
Dose Methotrexate ◽  
Grade 3 ◽  
Risk Of Relapse

Abstract Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and adolescents. Children with Down syndrome (trisomy 21) have a 30-times higher risk of acquiring ALL and pose up to 5% of all pediatric ALL patients. Moreover, many Down syndrome-ALL patients (DS-ALL) suffer from severe toxicity during chemotherapy, especially after application of high dose methotrexate (HD-MTX). Severe toxicities often result in MTX dose reduction, which may be associated with a higher probability of relapse. Systematic and comprehensive toxicity data in a large cohort of uniformly treated DS-ALL patients are lacking. In order to extend our knowledge on MTX-associated toxicities in DS-ALL, we analyzed clinical data from 103 DS-ALL and 1109 Non-DS-ALL (NDS-ALL) patients diagnosed between 1995 and 2016 treated according to German ALL-BFM protocols (ALL-BFM 1995, ALL-BFM 2000 and AIEOP-BFM ALL 2009). We only included patients for whom both therapy and toxicity data were available. We focused on toxicity after HD-MTX administration during the 8-week HD-MTX consolidation in which patients receive 4 courses of intravenous HD-MTX (5 g/m2 each) plus intrathecal MTX in addition to 6-mercaptopurine (25 mg/m2/d). As of 2004, it was recommended for DS-ALL to administer the first MTX course with a reduced dose of 0.5 g/m2 and subsequently increase the dose if no severe toxicity occurs. Toxicity grading was performed according to CTC 2.0. From the 103 DS-ALL patients four switched to high risk treatment and in one patient only incomplete data on toxicity were available. For these patients data could not be analyzed throughout the complete consolidation therapy. From the remaining 98 patients, 42 (43%) received MTX in a dose of 5 g/m2 ± 10%, six (6%) in a dose between 0.551 - 4.499 g/m2 and50 (51%) received a dose of 0.5 g/m2 ± 10% in the first MTX-block. In contrast, 1061 of 1109 (96%) NDS-ALL received an MTX dose of 5 g/m2. One DS-ALL patient died due to a severe infection after the second MTX block and in two DS-ALL patients HD-MTX consolidation was stopped due to severe infections after the first and the third MTX block, respectively. In contrast, HD-MTX was stopped for two NDS-ALL patients due to toxicity (neurotoxicity and infection) after the second and third course, respectively. All five patients received a first MTX dose of 5 g/m2. No NDS-ALL patient died during HD-MTX therapy. After receiving an MTX dose of 5 g/m2 DS-ALL showed significantly higher rates of grade 3/4 leukopenia, stomatitis, thrombocytopenia and infections as compared to NDS-ALL after the first course (Figure A). Reduction of the initial MTX dose to 0.5 g/m2 significantly reduced the rate of stomatitis, thrombocytopenia and leukopenia in DS-ALL by more than 40% (Figure B). However, these patients still suffered significantly more often from grade 3/4 stomatitis and infections compared to NDS-ALL who received full dose MTX (Figure C). Moderate MTX dose escalation for DS-ALL who tolerated a low MTX dose in the first course and received a higher MTX dose in the second course (median MTX dose 1 g/m2) did not result in an increased rate of toxicity as compared to the first course. Importantly, for DS-ALL a reduced MTX dose of 0.5 g/m2 in the first MTX block was not associated with a higher five year-cumulative risk of relapse (CIR) compared to a dose of 5 g/m2 (CIR 0.08±.05 vs. 0.16±0.05, p=.37). Differences in MTX plasma levels at 42 h and 48 h after start of the MTX infusion did not explain the higher rate of toxicity in DS-ALL as compared to NDS-ALL as most DS-ALL patients who received a low MTX dose presented with significantly lower MTX plasma level than NDS-ALL controls who received high dose MTX (Figure D). Additionally, DS-ALL with MTX plasma levels lower than median level (<0.320 µmol/l) showed significantly higher rates of grade 3/4 stomatitis and infections than NDS-ALL with higher plasma levels (≥0.320 µmol/l, Figure E). Within the DS-ALL group high MTX plasma level were associated with significantly higher rates of grade 3/4 stomatitis and thrombocytopenia (Figure F). In summary, MTX dose reduction in the first MTX course led to significantly decreased toxicity in DS-ALL without increasing the risk of relapse, although toxicity was still higher as compared to NDS-ALL. As low MTX plasma levels in DS-ALL were associated with less toxicity, lower cut-offs for higher leucovorine doses and forced diuresis may further reduce MTX toxicity in this highly vulnerable group of patients. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Pharmacokinetics and Pharmacodynamics of High Dose Methotrexate in Children with Acute Lymphoblastic Leukemia and down Syndrome: a Case Cohort Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1626-1626
Author(s):  
T. Buitenkamp ◽  
R. Mathot ◽  
A. Vulto ◽  
A. Veerman ◽  
E. van Wering ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Lymphoblastic Leukemia ◽  
Serum Levels ◽  
High Dose ◽  
Severe Toxicity ◽  
Treatment Protocols ◽  
Dose Methotrexate ◽  
Increased Risk ◽  
Grade 3 ◽  
Dose Reductions

Abstract Children with Down Syndrome (DS) have an increased risk of developing leukemia, including both acute myeloid, as well as acute lymphoblastic leukemia (DS-ALL). DS ALL patients have a poorer tolerance for high-dose methotrexate (HD-MTX), which is one of the key components of ALL treatment. There are no specific dosing guidelines for HD-MTX in DS-ALL. As a result doses are frequently reduced. In this study the pharmacokinetics (PK) and pharmacodynamics of HD-MTX were studied retrospectively in DS-ALL patients in order to develop specific dosing guidelines. Only one study addressed MTX-pharmacokinetics (PK) in DS children (Garre et al, J Pediatrics 1987). They found that median MTX plasma concentrations, 42 hours after infusion, were significantly higher in 5 DS-ALL patients compared to 3 non-DS controls. A retrospective case-cohort study was performed with DS-ALL patients enrolled in treatment protocols DCOG ALL-8, -9 or -10 in 8 Dutch medical centers during the period Nov 1991-Dec 2006. MTX dosages varied from 2.0–5.0 gr/m2 in the different treatment protocols. Forty-four DS and 87 non DS-ALL patients were included. The latter were matched for treatment protocol, sex and body surface area. All DS-ALL patients had B-cell-precursor ALL, and the median diagnostic WBC was 8,8*109/L. MTX serum levels and toxicity data were collected from patient files. Toxicity was graded according to CTCAE v3.0. Population PK-models were fitted to data from all individuals simultaneously, using non-linear mixed effect modeling (NONMEM). The PK of MTX was described according to a two-compartment model with a first order elimination from the central compartment. A total of 468 HD-MTX courses were given to 44 DS and 87 non-DS children. In 20% of the DS-ALL patients doses were reduced, comprising 26/152 (17.1%) of MTX courses. In 18/26 courses, dose-reduction was electively initiated from the 1st course onwards, whereas in 8/26 courses dose-reductions were applied from the 2nd course onwards because of documented toxicity in the 1st course. Dose reductions did not occur in non DS-ALL patients (p&lt;0.001). The cumulative frequency of grade 3/4 gastro-intestinal toxicity (mucositis) was significantly higher in DS versus non-DS children (27.6% of courses vs. 4.1%; p&lt;0.001), including courses in which MTX was dose-reduced. Hemoglobin and WBC were significantly lower in DS-patients, but probably not clinically relevant, as the differences were small. The methotrexate clearance for DS-ALL patients was 5% lower than for non DS-ALL patients (p&lt;0.001). Area under the curve (AUC) and MTX serum levels at various time-points after HD-MTX infusion were not different between DS and non-DS children. Moreover, there was no correlation between AUC (range 276–2603 μmol/L*hr) and grade 3 and 4 gastro-intestinal toxicity (rs 0.17; p=0.15). In fact grade 3/4 toxicity occurred at the lowest AUC of 276 μmol/L*hr. Hence no safe AUC could be defined. To summarize, DS-ALL patients suffer from increased risk of severe mucositis, which could not be explained by differences in PK, but are most likely due to pharmacodynamic effects of MTX. Given that only one patient needed a dose-reduction after severe toxicity when being treated with MTX dosages of 1–3 gr/m2, it seems safe to treat DS children with moderately high dosages of MTX and adjust dose in individual cases in case of severe toxicity. However, in case of 5 gr/m2, 8 patients needed dose-reduction, and hence this dose is probably too high for DS patients.

Toxicity and Risk Factors Contributing to Delayed Methotrexate (MTX) Elimination in Adult/Elderly Patients (pts) Treated with High-Dose Methotrexate Therapy (HDMTX), a 2-Year, Single Center Survey.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2439-2439
Author(s):  
Stefan Schwartz ◽  
Peter Martus ◽  
Wolf-Dieter Ludwig ◽  
Renate Arnold ◽  
Markus Ruhnke ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Trials ◽  
Serum Creatinine ◽  
Liver Toxicity ◽  
Lymphoblastic Leukemia ◽  
Advanced Age ◽  
High Dose ◽  
Severe Toxicity ◽  
Urine Ph ◽  
Grade 3

Abstract HDMTX is a well-established regimen used in a variety of neoplasms, including acute lymphoblastic leukemia (ALL) or lymphoma (NHL). Risk factors contributing to a delayed MTX-elimination and toxicity have been studied in pediatric pts with HDMTX (Relling MV, J Clin Oncol 1994, 12: 1667–72). However, data are scarce on risk factors contributing to delayed MTX elimination in adult pts, on toxicities in elderly pts and from pts treated with HDMTX outside clinical trials. We assessed toxicities and risk factors in all non-pediatric pts treated with HDMTX at the Charité in 2003/04. 141 pts (age 16–81y, median 44y) received 614 HDMTX cycles (median dose MTX/m2: 3000mg, range 320–12000mg) for ALL (39), NHL (38), CNS-NHL (36), sarcoma or other solid tumor (28) within (69) or outside (72) clinical trials. In 99/614 (16%) of HDMTX cycles a 15–85% (median 50%) dose reduction was carried out due to renal dysfunction (58), severe toxicity of prior chemotherapy (18) or other reasons (23). Toxicities in 62/614 (10%) HDMTX cycles caused delays of 1–50 days (median 7 days) of scheduled therapy. 61/614 (10%) HDMTX cycles resulted in an increase of serum creatinine values above the upper limit of normal (ULN) (median of 112μmol/L, range 81–386μmol/L). Delayed MTX-elimination (MTX blood level >150μM 24h, >3μM 36h, >1μM 42h, >0.4μM 48h or >0.1μM 68h) occurred in 156/614 (25%) HDMTX cycles. Grade 3/4 toxicities were recorded in 224 (36%) cycles for leukopenia, 127 (21%) cycles for liver toxicity, 116 (19%) cycles for thrombocytopenia, 88 (14%) cycles for fever with neutropenia and 63 (10%) cycles for mucositis/gastrointestinal toxicity. Presence of a 3rd space and comedications with known interference with MTX elimination or nephrotoxic potential were associated with a delayed MTX elimination (p<0.01). Overweight (BMI≥25kg/m2), urine pH<7 at some time after HDMTX and presence of a 3rd space were associated with an increase of serum creatinine values above ULN (p≤0.05). Pts with delayed MTX elimination or an increase of serum creatinine above ULN were older compared to pts with regular MTX elimination (median age 51y vs. 30y and 54y vs. 35y, p<0.01). Pts receiving HDMTX outside clinical trials more frequently experienced delayed MTX elimination (p<0.01). HDMTX frequently causes grade 3/4 hematotoxicity and increases of serum creatinine. Delayed MTX elimination is associated with advanced age and therapy outside clinical trials. Improved supportive care strategies are needed, especially in pts with advanced age, to ensure predictable MTX-elimination and reduce toxicities associated with HDMTX.

Treatment of adolescents and young adults with Philadelphia negative acute lymphoblastic leukemia (AYA Ph-ALL) using a risk and response based protocol with extended intensification and high dose methotrexate: A report from a single center in Saudi Arabia.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18527-e18527 ◽  
Author(s):  
Saleem Eldadah ◽  
Wasil Jastaniah ◽  
Ahmad Alsaeed ◽  
Mohammed Burhan Abrar ◽  
Mohamed A. Abdelaal ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
Prophylactic Cranial Irradiation ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Free Survival ◽  
Dose Methotrexate ◽  
Improved Outcomes ◽  
Grade 3

e18527 Background: Studies have shown superior outcomes of AYA Ph-ALL when treated with pediatric or pediatric-inspired protocol. Since 2003 we used a modified Children’s Oncology Group (COG) protocol to treat AYA Ph-ALL aiming to improve outcomes. Methods: This study involved 67 consecutive patients aged 14-35 years with Ph-ALL diagnosed between October 2003 and March 2016. Patients with precursor B ALL, CNS1/CNS2, and negative day 29 minimal residual disease (MRD-) received single interim maintenance (IM) and delayed intensification (DI) (Arm B). While CNS3 or MRD+ patients received double IM and DI (Arm C). Patients with T cell ALL received double IM with high dose methotrexate (HDMTX) in IM#1, and double DI (Arm C+HDMTX). Dexamethasone was used in all patients but prophylactic cranial irradiation was not utilized. Results: Median age at diagnosis was 17 years with 24 (35.8%) 18 years and older. CR rate, induction death, relapse rate, 4 year event free survival (EFS) and overall survival (OS) were 93.7%, 4.5%, 19.4%, 71.4%±6.0 and 81.8%±5.0; respectively. Of the 57 patients with available MRD, 44 (77.2%) were MRD-. Day 29 MRD status significantly impacted the outcomes (EFS: 78.6%±6.8 vs. 49.2%±15.4; p = 0.007 and OS: 90.5%±4.5 vs. 49.4%±22.0; p = 0.04) for MRD- vs. MRD+ patients; respectively). Outcomes were not different for T (n = 21) vs. B (n = 46) phenotypes (EFS: 69.2%±7.6 vs. 75.6%±9.5; p = 0.57 and OS: 79.8%±6.5 vs. 85.7%±7.6; p = 0.98; respectively). Grade 3 and above toxicities were venous thromboembolism (VTE) in 9 (13.4 %), avascular necrosis (AVN) in 9 (13.4 %) and pancreatitis in 3 (4.5 %) patients. Four patients (6%) died in CR and 2 died with secondary AML. Conclusions: Improved outcomes were observed with OS rate exceeding 90% for MRD negative patients. Therapy was tolerated relatively well, however, AVN and VTE occurred frequently. This suggests that utilizing a modified COG backbone in AYA Ph-ALL patients up to 35 years of age is feasible, however, further modification is warranted to reduce toxicity and improve outcomes in MRD positive patients.

Increased Age at Diagnosis Has a Significantly Negative Effect on Outcome in Children With Down Syndrome and Acute Myeloid Leukemia: A Report From the Children’s Cancer Group Study 2891

2003 ◽  
Vol 21 (18) ◽  
pp. 3415-3422 ◽  
Author(s):  
Alan S. Gamis ◽  
William G. Woods ◽  
Todd A. Alonzo ◽  
Allen Buxton ◽  
Beverly Lange ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Down Syndrome ◽  
Myeloid Leukemia ◽  
Age At Diagnosis ◽  
High Dose ◽  
Children With Down Syndrome ◽  
Cancer Group ◽  
Negative Effect ◽  
Grade 3 ◽  
Acute Myeloid

Purpose: To determine the outcome of children with Down syndrome (DS) and acute myeloid leukemia (AML) receiving standard timing chemotherapy without bone marrow transplantation (BMT), with determination of prognostic factors. Patients and Methods: Children with DS and newly diagnosed AML or myelodysplasia were prospectively enrolled on Children’s Cancer Group study 2891 (N = 161) and treated uniformly with four standard timing induction courses of dexamethasone, cytarabine arabinoside, 6-thioguanine, etoposide, daunorubicin (DCTER) followed by intensively timed high-dose cytarabine. Results: Children with DS were significantly younger at diagnosis than those without (median age, 1.8 v 7.5 years, respectively; P < .001), with more megakaryocytic leukemia (70% v 6%; P < .001). Higher complete remission rates (91%) were achieved in children with DS than among those without DS (75%; P < .001). Equivalent grade 3 to 4 toxicity (29% v 30%; P = .84) was seen, though children with DS had greater pulmonary toxicity (P < .01) during induction and mucositis during intensification (P = .12). Children with DS had significantly better 8-year event-free survival (EFS; 77% v 21% standard and 40% intensive induction; P < .0001). Multivariate analysis in children with DS revealed that only age at diagnosis of 2 years or older was a risk factor for greater relapse risk (odds ratio, 4.9; P = .006) and worse survival. Children between ages 0 to 2 years (n = 94) had a 6-year EFS of 86%; those from 2 to 4 years (n = 58), 70%; and those older than 4 years (n = 9), 28%. Remission failures were the primary reason for worse 6-year EFSs (1% in those 0 to 2 years v 14% if >2 years; P = .002). Conclusion: Outcome for children with DS and AML is excellent with standard induction therapy, but declines with increasing age.

scholarly journals Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort

2021 ◽  
Author(s):  
Riitta Niinimäki ◽  
Henri Aarnivala ◽  
Joanna Banerjee ◽  
Tytti Pokka ◽  
Kaisa Vepsäläinen ◽  
...  
Keyword(s):  
Folinic Acid ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Optimal Dosage ◽  
High Dose Methotrexate ◽  
Reduced Dose ◽  
Dose Methotrexate ◽  
Antileukemic Effect ◽  
Folinic Acid Rescue ◽  
High Doses

Abstract Purpose Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity. Methods We reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected. Results Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given. Conclusion A pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.

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