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

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<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<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<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.

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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 ◽

10.1182/blood-2018-99-112114 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1378-1378 ◽

Cited By ~ 1

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.

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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 ◽

10.1182/blood.v108.11.2439.2439 ◽

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.

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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.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e18527 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e18527-e18527 ◽

Cited By ~ 1

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.

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Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404)

Blood ◽

10.1182/blood-2010-06-292615 ◽

2011 ◽

Vol 118 (4) ◽

pp. 874-883 ◽

Cited By ~ 105

Author(s):

Barbara L. Asselin ◽

Meenakshi Devidas ◽

Chenguang Wang ◽

Jeanette Pullen ◽

Michael J. Borowitz ◽

...

Keyword(s):

T Cell ◽

Lymphoblastic Leukemia ◽

Randomized Study ◽

Lymphoblastic Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Oncology Group ◽

Dose Methotrexate ◽

Increased Risk ◽

The Difference

Abstract The Pediatric Oncology Group (POG) phase 3 trial 9404 was designed to determine the effectiveness of high-dose methotrexate (HDM) when added to multi-agent chemotherapy based on the Dana-Farber backbone. Children with T-cell acute lymphoblastic leukemia (T-ALL) or advanced lymphoblastic lymphoma (T-NHL) were randomized at diagnosis to receive/not receive HDM (5 g/m2 as a 24-hour infusion) at weeks 4, 7, 10, and 13. Between 1996 and 2000, 436 patients were enrolled in the methotrexate randomization. Five-year and 10-year event-free survival (EFS) was 80.2% ± 2.8% and 78.1% ± 4.3% for HDM (n = 219) versus 73.6% ± 3.1% and 72.6% ± 5.0% for no HDM (n = 217; P = .17). For T-ALL, 5-year and 10-year EFS was significantly better with HDM (n = 148, 5 years: 79.5% ± 3.4%, 10 years: 77.3% ± 5.3%) versus no HDM (n = 151, 5 years: 67.5% ± 3.9%, 10 years: 66.0% ± 6.6%; P = .047). The difference in EFS between HDM and no HDM was not significant for T-NHL patients (n = 71, 5 years: 81.7% ± 4.9%, 10 years: 79.9% ± 7.5% vs n = 66, 5 years: 87.8% ± 4.2%, 10 years: 87.8% ± 6.4%; P = .38). The frequency of mucositis was significantly higher in patients treated with HDM (P = .003). The results support adding HDM to the treatment of children with T-ALL, but not with NHL, despite the increased risk of mucositis.

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Pharmacokinetic analysis of high-dose methotrexate treatments in children with hematologic malignancies

Orvosi Hetilap ◽

10.1556/oh.2011.29143 ◽

2011 ◽

Vol 152 (40) ◽

pp. 1609-1617

Author(s):

Katalin Csordás ◽

Olivér Eipel ◽

Márta Hegyi ◽

Monika Csóka ◽

Éva Pap ◽

...

Keyword(s):

Lymphoblastic Leukemia ◽

Serum Levels ◽

Hematologic Malignancies ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

High Dose ◽

High Dose Methotrexate ◽

Serum Concentrations ◽

Toxicity Evaluation ◽

Dose Methotrexate

Monitoring the pharmacokinetic parameters of different anticancer drugs is necessary because they might have several side effects. Aim: Pharmacokinetic and toxicity evaluation of high-dose methotrexate treatments in children with acute lymphoblastic leukemia. Patients and methods: 43 children (28 boys, 15 girls, mean age: 7.03 years) in 147 cases were treated with 5 g/m2/24h MTX according to ALL-BFM 1995 and 2002 protocols. Methotrexate and 7-hydroxi-methotrexate levels were measured with high pressure liquid chromatography at 24, 36, 48 hours. Authors registered the development of hepatotoxicity, nephrotoxicity, grade III/IV oral mucositis. Results: Therapeutic methotrexate serum concentrations (30-100µmol/l) were achieved in 72.5% of the cases. Repeated treatments resulted similar serum levels. Hepatotoxicity and hypoproteinemia occurred in 17% and in 48.9% of the cases. There was significant correlation between serum 7-hydroxi-methotrexate and creatinine levels (p<0.05). Conclusion: 5 g/m2methotrexate resulted reliable therapeutic serum levels with mild and reversible toxicity. 7-hydroxi-methotexate measurements might be more useful than methotrexate levels to detect toxicity. Orv. Hetil., 2011, 152, 1609–1617.

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Feasibility of High-dose Methotrexate Administered on Day 1 of (R)CHOP in aggressive non-Hodgkin Lymphomas

Blood Advances ◽

10.1182/bloodadvances.2021005999 ◽

2021 ◽

Author(s):

Megan K Fleming ◽

Ying Huang ◽

Emily K Dotson ◽

David A Bond ◽

John C. Reneau ◽

...

Keyword(s):

Central Nervous System Involvement ◽

Kidney Injury ◽

Optimal Timing ◽

High Dose ◽

High Dose Methotrexate ◽

Treatment Delays ◽

Non Hodgkin Lymphoma ◽

Dose Methotrexate ◽

Grade 3 ◽

Dose Reductions

The optimal timing for administering high-dose methotrexate (HDMTX) when combined with (R)CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, with/without rituximab) is unclear. Recent data showed that the administration of prophylactic HDMTX before day 10 of R-CHOP may lead to fewer treatment delays. Herein, we report our experience with HDMTX administered on day 1 of (R)CHOP in patients with aggressive non-Hodgkin lymphoma. We identified 140 patients treated with ≥1 cycle of HDMTX combined with (R)CHOP for prophylaxis against (n=84) or treatment of (n=56) central nervous system involvement. Overall, (R)CHOP treatment delays ≥7 days (4% of cycles, 13% of patients), doxorubicin and/or cyclophosphamide dose reductions (1% of cycles, 6% of patients) or (R)CHOP discontinuations due to toxicity (4% of patients) were uncommon. Neutropenic fever (NF) occurred in 7% of cycles and 24% of patients and was more common during HDMTX-containing cycles. Acute kidney injury (AKI) occurred in 19% of cycles but was mostly grade ≤2. Grade ≥3 hepatotoxicity and mucositis were uncommon (each 2% of cycles). In the prophylaxis cohort, the rates of NF and grade ≥2 AKI were lower in patients who initiated HDMTX with cycle 2 or later (11% vs 30%, p=0.03 and 16% vs 39%, p=0.03, respectively). Our data show that HDMTX administration on day 1 of (R)CHOP may improve the deliverability of (R)CHOP and the overall safety of the regimen compared with historical data of HDMTX administration on day 10 or later of R-CHOP. Delaying prophylactic HDMTX beyond cycle 1 of (R)CHOP may reduce the risk of NF and AKI.

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Incidence, Predictors, and Significance of Severe Toxicity in Patients with HIV-Associated Hodgkin Lymphoma

Blood ◽

10.1182/blood.v112.11.2587.2587 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2587-2587 ◽

Cited By ~ 1

Author(s):

Hatoon Ezzat ◽

Matthew C Cheung ◽

Lisa K Hicks ◽

Kevin C Murphy ◽

Chantal S Leger ◽

...

Keyword(s):

Dose Reduction ◽

Hodgkin Lymphoma ◽

Opportunistic Infections ◽

Infectious Complications ◽

Hematologic Toxicity ◽

Severe Toxicity ◽

Hiv Viral Load ◽

Ct Dose ◽

Increased Risk ◽

Grade 3

Abstract Hodgkin lymphoma (HL) occurs in HIV-infected individuals more frequently than in the HIV-negative population and the incidence is rising. Patients (pts) with non-Hodgkin’s lymphoma in HIV appear to have improved outcomes if they receive HAART with chemotherapy (CT). ABVD is standard CT for HL and is frequently administered with HAART in pts with HIV-HL. However, some components of the ABVD regimen may interact with antiretroviral (ARV) medications to alter metabolism and increase toxicity. In particular, vinblastine (VBL) is metabolized by CYP3A4 and protease inhibitors, particularly ritonavir (RTV), appear to inhibit this cytochrome potentially leading to higher VBL exposure. Little definitive information is available regarding how interactions might affect clinical outcome. We conducted a retrospective review of 36 pts with HIV-related HL to identify the frequency of neurotoxicity (NT), hematologic toxicity (HT), and lung toxicity (LT), to identify risk factors for severe (grade III–IV) toxicity, and to determine its clinical significance. Clinical data were collected from the CFE database and by chart review from 3 centers. The median age at HL diagnosis (dx) was 41 (range 29–66) years and 34 (94%) were male. HL was advanced stage in 28 (78%). Hasenclever score could be calculated in 23 pts and was 0–4 and ≥5 in 15 and 8 pts respectively. ECOG PS was 0–1 in 13 and ≥2 in 8 (n=21). HIV risk factor was: sexual, n=21 and other, n=5 (n=26). Median CD4 count at HL dx was 210 (2–660) cells/ul (n=31). Median HIV viral load (VL) was undetectable (<50; range <50->500,000) copies/ml (n=25). Hepatitis B and C coinfection was present in 8 and 7 pts respectively (n=29). Prior AIDS was present in 23, all opportunistic infections. Twenty-four pts received HAART with CT. Primary HL CT was: ABVD, n=29 (81%); MOPP/ABV, n=4 (11%); palliative, n=3 (8%). G-CSF was used in 22 pts. All pts received prophylaxis for PCP and 3 for HSV/VZV. HAART included 17 Arts in numerous combinations. Infectious complications were: bacterial infection, n=6; febrile neutropenia, n=4; HSV, n=3; PCP, n=1. HT occurred in 21 (75%) of 28 assessable pts and was grade 3–4 in 18 (64%; 18 and 15 were on HAART, respectively). NT occurred in 14 (50%) pts and was grade 3–4 in 6 (21%; 13 and 5 on HAART respectively, n=28). Of 6 cases of severe NT, 3 were autonomic neuropathy with pseudobowel obstruction that in 1 pt resulted in perforation. Bleomycin LT occurred in 3 pts (n=26). CT dose reduction (DR) of ≥25% in ≥1 agent was required in 9 pts (n=26). Factors associated with grade 3–4 HT were: receiving RTV, p=0.04, HR 2.9 (95% CI 1.1–7.4); and receiving lopinovir (LPV), p=0.02, HR 7.0 (2.3–21.3) and for any HT were: RTV, p=0.004, HR 3.1 (1.3–7.3); emtricitabine, p=0.01, HR 4.8 (1.4–11.6); and LPV, p=0.04, HR 4.4 (1.6–12.1). Factors for grade 3–4 NT were: LPV, p=0.05, HR 10.8 (2.0–59.5) and for any NT was: RTV, p=0.01, HR 4.0 (1.3–12.1). Fourteen pts received RTV and of 8 receiving LPV, 7 received LPV with RTV (p=0.007). At a median follow-up of 15.3 (0.1–154.8) months (mo) 25 pts (69%) are alive. The median overall survival (OS) for all pts was 44.5 (2–154.8) mo and there was no difference in OS by baseline features or the occurrence of HT or NT. However, CT dose reduction was associated with inferior OS (p=0.04, HR 3.9 [1.0–15.7]); although only 1 of 9 deaths was from HL progression; others were: infectious, n=6; and unrelated, n=2. In conclusion, pts with HIV-HL appear to experience a significantly increased incidence of NT compared to rates reported in non-HIV HL pts. In contrast, rates of HT and LT appear to be similar to those in non-HIV HL. The use of RTV or LPV during CT appeared to be associated with an increased risk of NT, suggesting a clinically significant interaction between these ARV agents and CT, particularly VBL. Prospective studies to devise a rational dosing strategy using measurements of ARV and/or CT levels are warranted.

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

Supportive Care in Cancer ◽

10.1007/s00520-021-06395-3 ◽

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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