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.

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.

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.

High-dose cytosine arabinoside therapy for refractory leukemia

Blood ◽  
1983 ◽  
Vol 62 (2) ◽  
pp. 361-369 ◽  
Author(s):  
RH Herzig ◽  
SN Wolff ◽  
HM Lazarus ◽  
GL Phillips ◽  
C Karanes ◽  
...  
Keyword(s):  
Cytosine Arabinoside ◽  
Liver Toxicity ◽  
Lymphoblastic Leukemia ◽  
Skin Toxicity ◽  
Maximum Tolerated Dose ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Antileukemic Activity ◽  
Duration Of Treatment ◽  
Platelet Recovery

Abstract Fifty-seven patients with refractory acute leukemia were treated with high-dose cytosine arabinoside to establish the maximum tolerated dose and duration and to determine the antileukemic activity. The maximum tolerated regimen was found to be 3 g/sq m every 12 hr for 6 days. At this dose, nonhematologic toxicity was limited to conjunctivitis in approximately half of the patients, and liver toxicity (transient elevations in transaminase, alkaline phosphatase, or bilirubin) was frequently observed, but neither was dose-limiting. Extending the duration of treatment to 8 days resulted in excessive diarrhea and skin toxicity (painful erythema with bullae), while increasing the dose to 4.5 g/sq m q. 12 hr for 6 days resulted in severe cerebellar toxicity. Myelosuppression was severe, but was not related to the intensity of treatment; granulocyte recovery occurred a median of 28 days (range 22- 40 days) after initiating therapy, and platelet recovery occurred after a median of 25 days (range 16–41 days). Antileukemic activity was evaluable in the 46 patients who survived at least 3 wk. Complete remissions were obtained in 1 of 6 patients with chronic myelogenous leukemia (CML) in accelerated phase and 1 of 3 acute lymphoblastic leukemia (ALL) patients. A more detailed analysis of response was possible for the 37 evaluable patients with acute nonlymphoblastic leukemia: 70% of these patients responded, with 51% complete remissions. The median unmaintained response was 4 mo (range 2–26+ mo). The complete response rate was higher in patients who received at least 12 doses of high-dose cytosine arabinoside compared to shorter regimens [17/28 (61%) versus 2/9 (22%), p less than 0.05]. Resistance to cytosine arabinoside in conventional doses was documented in 11 patients, 5 of whom responded (2 complete remissions) to high-dose regimens. We conclude that high-dose cytosine arabinoside in the maximally tolerated regimen of 3 g/sq m every 12 hr for 6 days has substantial antileukemic activity in patients refractory to standard therapy. Durable unmaintained remissions can be achieved, even in patients who fail to respond to cytosine arabinoside in conventional doses.

Increased Incidence of Osteonecrosis (ON) with a Dexamethasone (DEX) Induction for High Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report from the Children’s Oncology Group (COG).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 898-898 ◽  
Author(s):  
Leonard A. Mattano ◽  
James B. Nachman ◽  
Meenakshi Devidas ◽  
Naomi Winick ◽  
Elizabeth Raetz ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Initial Study ◽  
Intrathecal Methotrexate ◽  
High Dose ◽  
Historical Comparison ◽  
Randomized Design ◽  
Age Cohort ◽  
Methotrexate Dose ◽  
Grade 3 ◽  
The Impact

Abstract Treatment with DEX, rather than prednisone (PRED), improves outcome for children with standard risk ALL. However, DEX exposure is strongly associated with the development of therapy-related ON, particularly in adolescents. Previous COG HR-ALL studies have shown a lower ON risk for patients receiving 1 vs. 2 delayed intensification (DI) phases, and for DI using discontinuous DEX (days 1–7 & 15–21) vs. continuous DEX (days 1–21), suggesting a strategy for giving the drug with acceptable toxicity. The HRALL study COG AALL0232 utilizes a modified augmented BFM backbone that compares in a 2x2 randomized design: induction DEX (10 mg/M2/day x14 days) vs PRED (60 mg/M2/day x28 days), and interim maintenance (IM) escalating-dose “Capizzi” methotrexate vs. high-dose (HD) MTX. Induction rapid early responders (RER) receive single DI while slow responders receive double DI; all patients receive monthly 5-day DEX pulses during maintenance. To limit ON risk in adolescents, in the initial study design children ≥ 13y received discontinuous DEX during single or double DI; those <13y received continuous DEX. In 10/2006 the study was amended due to an unexpectedly high ON incidence in patients 10–12y receiving continuous DEX (28% @ 18 months) compared with historical controls given discontinuous DEX (3.4%). Subsequently all patients ≥ 10y have received discontinuous DEX; it is too early to assess the impact of this change. A comprehensive interim ON analysis was completed 4/2008 (reported as 24-month cumulative incidences). Overall ON incidence is 10.4% (110/1647), and is higher for those age ≥ 10 vs. <10y (15.2 vs 2.6%, p<0.0001, RHR=6.38); 99/110 cases of ON occurred in the older cohort. Among all patients, ON incidence is higher in DEX vs. PRED regimens (11.6 vs 8.7%, p=0.014, RHR 1.64); rates are similar for Capizzi MTX vs. HD-MTX regimens (10.4 vs 9.8%). Among patients ≥ 13y, incidence is higher in DEX vs. PRED regimens (18.9 vs 9.9%, p=0.02, RHR 1.97). There is no difference between regimens for children <10y. Among randomized RER patients ≥ 10y, incidence is higher in DEX vs. PRED regimens (17.2 vs 12.6%, p=0.006, RHR=1.79). For historical comparison, ON incidences by age cohort for RER patients on AALL0232 regimen PC (PRED + Capizzi MTX) vs. CCG-1961 regimen D (double DI with discontinuous DEX) were: <10y 4.1±3.4 vs. 2.0±1.4%, 10–12y 21.9±10.6 vs. 7.1±2.8%, and ≥ 13y 7.1±10.1 vs. 6.6±3.8%. To address these findings, the study was amended 6/2008. Patients ≥ 10y will be non-randomly assigned to induction PRED; the induction steroid randomization will continue for younger patients. Patients of all ages will receive discontinuous DEX during DI and PRED pulses during maintenance. Of note, compared with CCG-1961 the AALL0232 augmented BFM backbone was non-randomly modified in several ways that may affect ON incidence, including the use of pegaspargase during induction, a higher 15 mg intrathecal methotrexate dose for those age ≥ 9y, and monthly DEX instead of PRED maintenance pulses. Heightened awareness among caregivers may also have led to increased recognition and reporting of this toxicity. Using CTCAE v3.0 criteria, clinical ON severity among the 110 patients is: 3% grade 1, 60% grade 2, 35% grade 3, and 2% grade 4. Data regarding surgical intervention are being collected. These findings will directly influence the design of future trials in an effort to lessen the incidence and burden of this toxicity.

Effects of Dexamethasone (DEX) Vs Prednisone (PDN) and High-Dose Methotrexate (HD-MTX) Vs Capizzi Methotrexate/Asparaginase (C-MTX/ASNase) On Osteonecrosis (ON) Incidence in Children and Young Adults with High Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report From the Children's Oncology Group (COG) Study AALL0232

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 665-665 ◽  
Author(s):  
Leonard A. Mattano ◽  
Meenakshi Devidas ◽  
Naomi Winick ◽  
Elizabeth Raetz ◽  
Stephen P. Hunger ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Significant Risk ◽  
Pairwise Comparison ◽  
Clinical Severity ◽  
High Dose ◽  
Additional Risk ◽  
History Of ◽  
Children And Young Adults ◽  
Grade 3

Abstract Abstract 665 Improved treatment outcomes for HR-ALL are associated with a significant risk of symptomatic ON, particularly in adolescents. Causes are multifactorial, including exposure to DEX, MTX and ASNase. This was first noted on CCG-1882 (1991–1995), which showed more ON in slow early responders (SER) given 2 vs 1 interim maintenance/delayed intensification (IM/DI) phases as part of therapy that included C-MTX/ASNase during IM and continuous DEX (d1-21) during DI (Mattano, JCO 2000). Since 1996 the COG has prospectively monitored the occurrence of symptomatic ON in HR ALL trials. CCG-1961 (1996–2002) showed that alternate-week DEX (AWD) (d1-7, 15–21) during 2 DIs reduced ON compared with continuous DEX during 1 DI in rapid early responders (RER) (Mattano, Lancet Oncol 2012). AALL0232 (2003–2011) enrolled a total of 3154 HR-ALL patients (pts) 1–30 yr and included COG augmented therapy with a 2×2 randomization to DEX (10 mg/M2 d1-14) vs PDN (60 mg/M2 d1-28) during induction (IND) and HD-MTX vs escalating-dose C-MTX plus pegaspargase during IM. RER pts received 1 IM/DI, SER pts received 2 IM/DI; all initially received monthly DEX maintenance (MTC) pulses (6 mg/M2 d1-5). To limit ON, pts 13+ yr received AWD during 1 or 2 DI, while pts <13 yr received continuous DEX. Based on interim analyses, the study was amended twice to address unexpectedly high ON rates. After 10/2006 all pts 10+ yr received AWD during DI; after 6/2008 all pts 10+ yr were non-randomly assigned to PDN during IND, and pts of all ages received AWD during DI and PDN pulses in MTC. Detailed analyses of 2701 pts with reportable data (1405 with 24+ month follow-up) showed ON in 249 pts (228 10+ yr, 21 1–9 yr; 119 males, 130 females). Symptom onset was pre-MTC in 17.7%, during MTC in 77.9%, after therapy completion in 4.4%, and within 36 months from ALL diagnosis in 98.0%. The 36-month cumulative ON incidence was 13.5±1.1%, was higher for pts 10+ yr (19.6±1.6 vs 3.1±0.9%, RHR 6.7, p<0.0001), and increased with age (1–9 yr 3.1±0.9%, 10–12 yr 17.2±2.5%, 13–15 yr 21.9±2.7%, 16+ yr 21.2±3.3%, p<0.0001). For pts 10+ yr, ON incidence was higher in females (22.2±2.5 vs 17.4±2.1%, RHR 1.4, p=0.01). Among randomized RER pts 10+ yr (Table), ON incidence was higher for DEX vs PDN (RHR 1.8); for pts 1–9 yr, rates were similarly low but modestly higher for PDN (borderline significance). There was no difference between C-MTX/ASNase vs HD-MTX overall. However, for pts 10+ yr randomized to PDN, pairwise comparison showed a higher ON rate for C-MTX/ASNase (17.2±3.8 vs 10.3±2.7%, RHR=1.7, p=0.01). Comparison of ON incidences between randomized RER regimens showed significant differences in pts 1–9 yr (DC 1.5±1.4, DH 0.7±1.0, PC 5.6±2.6, PH 1.9±1.6%, p=0.04) and 10+ yr (DC 23.9±4.0, DH 24.7±3.7, PC 20.9±4.0, PH 9.8±2.7%, p=0.0004). Comparison of ON incidences for pts 10–12 yr given continuous DEX vs AWD in DI (pre- vs post-2006 amendment) confirmed a significantly lower rate with AWD (28.9±3.8 vs 10.3±3.1%, RHR 3.1, p<0.0001). Maximum patient ON clinical severity (CTCAE v3.0) reported for 210 of 249 pts: 6.7% grade 1, 63.3% grade 2, 29% grade 3, 1.0% grade 4. The most common sites were knee > hip > ankle. In conclusion, DEX is associated with a higher incidence of ON among pts 10+ yr receiving augmented therapy. Children 1–9 yr appear to tolerate DEX and PDN during IND with similar low ON rates. ON risk can be significantly reduced by using AWD during DI, and by using HD-MTX rather than C-MTX/ASNase with PDN based regimens. Studies are presently underway that include prospective MRI screening to further define the natural history of ON in HR ALL and to identify additional risk factors for this common toxicity. Randomized RER, 36-Month Incidence Rate (% ± SE) DEX PDN P 1-9 yr 1.1 ± 0.9 3.7 ± 1.5 0.05 10+ yr 24.3 ± 2.7 15.1 ± 2.4 0.0007 16+ yr 25.6 ± 6.0 13.7 ± 4.9 0.04 C-MTX HD-MTX P 1-9 yr 3.6 ± 1.4 1.6 ± 0.9 0.09 10+ yr 19.1 ± 2.4 18.3 ± 2.2 0.4 16+ yr 16.4 ± 4.7 24.0 ± 4.5 0.2 Disclosures: Mattano: Pfizer: Employed 2009–2012 Other, Equity Ownership.

CNOT1 Microrna Single Nucleotide Polymorphism (SNP) Determines the Occurrence of Methotrexate Related Mucositis in Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1237-1237
Author(s):  
Natanja Oosterom ◽  
Ángela Guttiérez-Camino ◽  
Marissa Den Hoed ◽  
Elixabet López-López ◽  
Saskia MF Pluijm ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Candidate Snps ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All ◽  
Grade 3 ◽  
And Function

Abstract BACKGROUND Cure rates of pediatric acute lymphoblastic leukemia (ALL) have reached 90% in the developed countries. However, toxicity due to chemotherapeutic regimens occurs frequently but with great heterogeneity. This suggests that genetic variation is involved. In order to identify determinants of adverse effects, recent studies have investigated pharmacogenetic features in relation to toxicity. Most of these studies examined coding regions of the genome. Recently, it has been described that epi genetic regulators, such as micro-RNA's (miRNA), might also have an important regulatory function in genes involved in drug related toxicity. In a recent study 25 miRNA SNPs were found to be related to toxicity in pediatric ALL treatment (Lopez-Lopez, PLoS ONE, 2014). In pediatric ALL mucositis is one of the most frequent side effects during high dose methotrexate (MTX) treatment. AIM The aim of this study was to detect novel, epigenetic biomarkers that predict MTX related oral mucositis in pediatric acute lymphoblastic leukemia (B- and T cell) by studying single nucleotide polymorphisms (SNP) involved in miRNA levels and function. METHODS DNA was isolated from whole blood of 118 pediatric ALL patients that were treated with high dose MTX (5 gr/m2) according to the Dutch Childhood Oncology Group ALL-10 protocol. The recently published 25 SNPs, involved in miRNA function and located in the DROSHA, CNOT1, CNOT4, EIF2C1, GEMIN3, GEMIN4, MIR604, MIR453, MIR2110, MIR2053, MIR1294, MIR1206, DICER, XPO5 and TNRC6B genes, were selected for genotyping. Toxicity data during the consolidation phase were prospectively collected and documented according to the National Cancer Institute (NCI) v.3.0 score system. Mucositis NCI grade ≥ 3 (grade 3: confluent ulcerations, bleeding with minor trauma), was considered as clinical significant toxicity and was used as endpoint. RESULTS Mucositis was the only recurring toxicity in this prospectively well-documented cohort and therefore used as endpoint of this study. A selection of 20 of the previously identified 25 candidate SNPs was studied based on technical feasibility. In addition, 1 SNP in the XPO 5 gene was not considered for analysis because it was not in Hardy Weinberg equilibrium. Mucositis occurred in 19% of the patients in at least one of the MTX courses. Only the TT genotype of rs11866002 in the CNOT1 (CCR4-NOT complex, subunit 1) gene was associated with a higher risk of developing mucositis (NCI ≥ 3) compared to carries of CC/CT. The other 18 candidate SNPs analyzed did not show statistically significant associations. CONCLUSION The inter-patient variability of mucosal toxicity was not associated with most of our investigated SNPs which are involved in miRNA transcription and function. CNOT1 rs11866002 C>T was the only single nucleotide polymorphism associated with the occurrence of oral mucositis during pediatric acute lymphoblastic leukemia treatment. We acknowledge the Foundation Children Cancerfree (KiKa), Amstelveen, The Netherlands, for funding this research. Disclosures No relevant conflicts of interest to declare.

Nilotinib Combined with Multi-Agents Chemotherapy for Adult Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of a Prospective Study from a Single Center

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1301-1301
Author(s):  
Bingcheng Liu ◽  
Ying Wang ◽  
Chunlin Zhou ◽  
Hui Wei ◽  
Dong Lin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Maintenance Therapy ◽  
Prospective Study ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Induction Cycle

Abstract Background: Imatinib combined with conventional chemotherapy has significantly improved the prognosis of adults with Philadelphia-positive acute lymphoblastic leukemia ( Ph+ ALL ). Nilotinib, the second generation TKIs is approximately 30 fold more potent than imatinib and is active in vitro against multiple BCR/ABL mutations. Here, we report the efficacy and safety of nilotinib combined with multiple reagents chemotherapy in newly diagnosed patients with Ph+ ALL. Methods: Newly diagnosed Ph+ ALL patients aged 15 to 59 and with adequate organ function were recruited. The 4weeks induction cycle consist of vincristine, daunorubicin, cyclophosphamide and prednisone. After achieving hematological complete remission (HCR), patients received 2 years of consolidation and maintenance therapy. Consolidation therapy was including 7 courses of multiple drug chemotherapy or allogeneic/autologous hematopoietic cell transplantation (allo/auto HCT). Nilotinib was the only drug for maintenance therapy. Nilotinib 400mg was given orally twice daily along with combination chemotherapy starting from day 15 of induction until the initiation of conditioning for transplantation, hematological relapse or continuing for 2 years since achievement of hematological complete remission (HCR).Central nervous system (CNS) prophylaxis was performed by intrathecally administering triple agents. The data cut-off day was June 1st 2015. HCR and molecular complete remission (MCR), overall survival(OS), hematologic relapse free survival (HRFS), toxicity, nilotinib concentration in serum and cerebrospinal fluid(CSF) were evaluated. MCR was defined as Bcr-Abl fusion gene becomes negative in bone marrow using quantitative RT-PCR. Results: A total of 30 patients (19 males and 11 females) were enrolled from September 2011 to November 2013. The median age was 40 (range 21-57) years old. The type of BCR breakpoint was minor in 24 patients, major in 2 patients and both in 4 patients. All the 30 patients (100%) and 8 patients (26.7%) achieved HCR and MCR respectively after the induction cycle. Cumulative MCR rate was 80%. 17 patients underwent HCT, 14 patients with alloHCT and 2 patients with autoHCT in first HCR, 1 patient received alloHCT after relapse. 9 patients died from leukemia relapse and 4 patients died post-alloHCT without relapse. The median HRFS and OS were 20.7 and 34 months respectively. The 4 year HRFS rate was 41% and the 4 year OS rate was 48%. The molecular response after induction has no impact on HRFS and OS. Patients achieving MCR had better HRFS (32 vs 8.9 months, p=0.006) but not OS(33.3vs 17.2months, p=0.068) than those patient without MCR. During induction, 23 patients experienced infectious fever including 2 patients with septicemia and 6 patients with pneumonia needing antifungal therapy. Intestinal obstruction occurred in 7 patients during induction and relived by interrupting nilotinib treatment. The incidence of non-hematologic adverse events (AE) over grade 3 during the study was 23% jaundice, 10% rash, 6.7% arthralgia and bone pain, 6.7%headache, 3.3% ALT elevation. No QTc prolongation over 500ms happened. Grade 2 tachycardia and premature ventricular contraction occurred in 2 patients and 1 patient respectively. During the high-dose methotrexate treatment cycle, delaying of methotrexate metabolism happened in 20 patients (66.7%), increasing creatine occurred in 8 patients (26.7%, grade 3 in 3 patients), 1 patient received haemodialysis. Nilotinib serum level reached to stable concentration after 15 days of administration. Only traces of nilotinib was detected in CSF. Conclusion: In this prospective study, combination of nilotinib and cytotoxic drug was shown to be effective and tolerable for adult Ph+ALL. Nilotinib could not penetrate the blood brain barrier. (ChiCTR-ONC-12002469) Disclosures Off Label Use: nilotinib,the 2nd generation TKI, was approved for CML. Wang:Novarits and Bristol-Mayers squibb. G.S.: Consultancy.

Risk factors for oral mucositis (OM) in multiple myeloma (MM) patients receiving high-dose melphalan (Mel) prior to autologous stem cell transplantation (SCT).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19565-e19565
Author(s):  
Bhavana Bhatnagar ◽  
Olga G. Goloubeva ◽  
Steven Gilmore ◽  
Arnold Hoffman ◽  
Kathleen Ruehle ◽  
...  
Keyword(s):  
Risk Factors ◽  
Hospital Stay ◽  
Oral Intake ◽  
Length Of Hospital Stay ◽  
High Serum ◽  
P Value ◽  
High Dose ◽  
Grade 3 ◽  
High Dose Melphalan ◽  
The Impact

e19565 Background: OM is a common complication of high-dose melphalan in MM patients (pts). Proposed risk factors for OM in SCT include: low albumin and high serum creatinine (Cr) levels, both were evaluated in MM patients undergoing Mel/ASCT. (Grazziutti, ML, Bone Marrow Transplant 2006). Methods: This is a single center retrospective chart review of 214 sequentially treated MM pts who received Mel 200mg/m2 conditioning prior to SCT between January 2005-September 2011. Data collected included: demographics, Hgb, Cr, C-reactive protein and albumin on the day of SCT, length of hospital stay. OM assessment was graded as follows: Grade 1, no OM; Grade 2, mild OM; the pts maintained adequate oral intake; Grade 3, decreased oral intake and/or use of oral narcotics; Grade 4, severe OM needing intravenous narcotics. Results: The table below describes pt characteristics grouped by OM grade. Overall, 56 pts (27%) had grade 3/4 OM. Multivariate analysis of variance revealed no statistically significant correlation between OM grade and Hgb, Cr, albumin, CRP; the overall test’s p value = 0.55. There were no racial or gender differences with regard to grade of mucositis, the p-values range are 0.75 and 0.31, respectively (likelihood ratio chi-square test). Most interestingly, OM did not impact length of hospital stay. Conclusions: We did not establish any predictive risk factors for OM as previously described. Analysis of the impact of OM on MM response and event and overall survival will be presented. Studies of Mel pharmacogenetics may provide insight to patients' predisposition to OM. [Table: see text]

scholarly journals Incidence and Risk Factors for Vancomycin Nephrotoxicity in Acutely Ill Pediatric Patients

2017 ◽  
Vol 34 (1) ◽  
pp. 9-16 ◽  
Author(s):  
Henock Woldu ◽  
B. Joseph Guglielmo
Keyword(s):  
Risk Factors ◽  
Confidence Interval ◽  
Serum Creatinine ◽  
Odds Ratio ◽  
Kidney Injury ◽  
Severe Toxicity ◽  
Vancomycin Trough ◽  
Trough Concentrations ◽  
The Mean ◽  
Mean Time

Background: Particularly with the current increased vancomycin dosing trends, the true risk of the agent’s nephrotoxicity is not well characterized and remains of concern. Objective: To determine the incidence of vancomycin nephrotoxicity in acutely ill hospitalized children and to secondarily characterize the risk factors for this complication. Methods: A single-center retrospective cohort study conducted at UCSF Benioff Children’s Hospital from June 2012 to June 2015. Inpatients 3 months to <19 years who received intravenous vancomycin for ≥48 hours were included. The primary outcome was incidence of nephrotoxicity, defined as an increase in serum creatinine by ≥50% from baseline. Univariate and multivariate analyses were conducted to identify risk factors for vancomycin nephrotoxicity. Results: A total of 291 patients (272 nonnephrotoxic and 19 nephrotoxic) were included in the analysis. Of the 19 patients, 12 (4.1%) were found to have moderate to severe toxicity. The median duration of therapy was 3 (3-5) and 4 (3-6) days for the group with “no nephrotoxicity” and “nephrotoxicity,” respectively. The mean time for the serum creatinine to return to normal in patients with nephrotoxicity was 5.1 days. In the multivariate analysis, only final trough concentration ≥15mg/dL (odds ratio = 3.49, 95% confidence interval = 1.2-10.1; P = .021) and receipt of piperacillin/tazobactam (odds ratio = 3.14, 95% confidence interval = 1.02-9.6; P = .046) were significantly associated with nephrotoxicity. Conclusion: The rate of moderate to severe vancomycin-associated nephrotoxicity in acutely ill children is relatively uncommon and reversible. Kidney injury is associated with increased vancomycin trough concentrations and concomitant receipt of nephrotoxins, particularly piperacillin/tazobactam.

scholarly journals Factors affecting colistin nephrotoxicity: Advanced age and/or other factors?

2021 ◽  
Author(s):  
Tugba Arslan Gülen ◽  
Ayfer Imre ◽  
Uner Kayabas
Keyword(s):  
Risk Factors ◽  
General Population ◽  
Serum Creatinine ◽  
Serum Creatinine Level ◽  
Creatinine Level ◽  
Geriatric Patients ◽  
Advanced Age ◽  
Factors Affecting ◽  
Factors Associated ◽  
Independent Risk Factors

Introduction: The population is aging and older adults comprise the majority of patients in intensive care units. Colistin (COL) has been reintroduced to treat increasingly common resistant Gram-negative bacterial infections. Our study aims to investigate the factors affecting colistin nephrotoxicity in the general population and geriatric age group. Materials and Method: This retrospective study included 170 patients, 116 (68.2%) of which were in the geriatric group (age ≥65). Acute renal failure was evaluated using the RIFLE score. Firstly, factors associated with COL nephrotoxicity in the general population were investigated. Then, risk factors for COL nephrotoxicity were evaluated in the geriatric patient group. Results: Advanced age (odds ratio [OR]=1.043; 95% confidence interval [CI]: 1.018-1.068; p=0.001) and initial serum creatinine level (OR=23.122; 95% CI: 3.123-171.217; p=0.002) were found to be independent risk factors associated with nephrotoxicity. In the evaluation of the geriatric population-based on nephrotoxicity, the initial serum urea and creatinine levels, immunosuppression, and overall mortality rates were found to be statistically significant in the group with nephrotoxicity (p<0.05). Initial serum creatinine level (OR=22.48; 95% CI: 2.835-178.426; p=0.003) and concomitant nephrotoxic agent use (OR=2.516; 95% CI: 1.275-4.963; p=0.008) were independent risk factors associated with nephrotoxicity in geriatric patients. Conclusion: Advanced age was found to be a risk factor for COL nephrotoxicity. Caution should be exercised especially in geriatric patients who have initial serum creatinine levels close to the upper limit, concomitant use of nephrotoxic drugs should be avoided and if possible, evaluation should be made in terms of non-COL treatment options in these patients.

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