High-dose Methotrexate Toxicity Research Articles

Mutational Status in Genes of Folate Metabolism Is Associated with Toxicity of High-Dose Methotrexate in Patients with Immunocompetent Primary Central Nervous System Lymphoma.

Background: Outcome of patients with immunocompetent primary central nervous system lymphoma (PCNSL) has improved since the introduction of high-dose (HD) methotrexate (MTX). However, treatment may be perturbed by considerable toxicity. Acute toxicity comprises hematologic, renal, hepatic, pulmonary events and mucositis while neurologic impairment is essentially restricted to long-term survivors. MTX acts via inhibition of 5,10-methylentetrahydrofolate reductase (MTHFR) as well as thymidylate synthase (TYMS) in target cells what eventually results in decreased DNA synthesis. Intracellular uptake of folates is mediated by the reduced folate carrier (RFC). Two common MTHFR single nucleotide polymorphisms (SNPs) affect enzyme activity: 677 C→T and 1298A→C. A 28 base pair (bp) tandemly repeated sequence in the TYMS enhancer region (5′-UTR) containing either 2 or 3 repeats alters enzyme activity as does a 6 bp deletion (del) polymorphism in the 3′-UTR of TYMS. An RFC SNP (80G→A) is known to influence folate and MTX transport. We hypothesized that these polymorphisms may be directly linked to toxicity in PCNSL patients receiving high-dose MTX.Patients and methods: Genomic DNA was prospectively collected from patients (pts) with immunocompetent PCNSL who received HD MTX 4 g/m² every 2 weeks after enrolment onto a German multicenter trial. They had to have histological confirmation of their disease as well as adequate organ and bone marrow function. Genotyping of the two MTHFR and the RFC SNPs was performed by melting point analysis using the Light Cycler® technology. Genotyping of the TYMS 28bp polymorphism was performed by conventional PCR followed by agarose gel electrophoresis. The TYMS 6bp del polymorphism was analyzed by PCR, restriction enzyme digest and agarose gel electrophoresis. Hematologic (Hb, WBC, ANC, platelets) and non-hematologic toxicity (renal, hepatic, pulmonary, mucositis) were assessed prospectively and correlated with polymorphisms with respect to presumable functional relevance.Results: 123 pts with a median age of 62 (range, 27 – 80) years received a total of 506 cycles of high-dose MTX. 39 of 119 evaluable pts (33%) experienced any severe (°3/4) toxicity. Incidence of severe toxicity was significantly different for pts with MTHFR 677 TT (95%) when compared to CC/CT genotype (48%; p=.0024). Not considering hematologic parameters, severe toxicity was even more strongly associated with homozygosity for 677TT (p=.0006). A moderate association with lower ANC was found for MTHFR C677T (p=.049) while °3/4 neutropenia was strongly associated with RFC 80 GG vs. AA/GA (p=.0057). In hand, lower WBC nadirs occurred in pts with RFC 80 GG vs. AA/GA (p=.035).Conclusion: We demonstrate for the first time that pharmacogenetic studies might identify PCNSL pts who are at risk for severe acute hematologic and non-hematologic toxicity when treated with HD MTX. Correlation of (late) neurotoxicity with polymorphisms of folate metabolizing genes, however, will require longer follow-up.

A multicentric prospective study of intensive induction chemotherapy (API-AI) in localized osteosarcoma patients: Results of a phase II trial coordinated by the French Sarcoma Group (FSG) and the FNCLCC BECT

9521 Background: Based on the severe toxicity of high dose methotrexate (MTX) in adult patients, an alternative intensive chemotherapy (CT) was designed, associating doxorubicin, cisplatinum and ifosfamide in API-AI regimen. Promising results in 32 patients in a single institution study (Le Cesne ASCO 2004) led to a national multicenter phase II trial coordinated by the FSG of FNCLCC. Methods: Patients with a localized operable osteosarcoma were eligible. API-AI regimen consisted in 2 cycles every 28 days of doxorubicin 60 mg/m2 d1 and d15, cisplatinum 100 mg/m2 d1 and ifosfamide 5g/m2 d2 and d15, with equivalent dose of mesna and lenograstim after each course for 7 days. Good responders ≥95% necrosis (GR) received 2 postoperative API courses, and poor responders <95% necrosis (PR) a salvage regimen of 3 cycles of etoposide 100 mg/m2 d1 to d3 and ifosfamide 4 g/m2 d1 to d3. Results: From March 2001 to January 2004, 43 patients (male/female 28/15) with a median age of 23 years (range 17–50), were included. The median tumor size was 88 mm (13–280). All 43 patients received the preoperative API-AI regimen, with a dose intensity of ≥ 89% of the planned protocol. Toxicity was mainly haematological, with grade 3–4 sepsis, grade 4 neutropenia and thrombocytopenia observed in 12%, 79% and 49% of patients respectively. There was no severe renal and cardiac toxicity. All but 5 patients had a limb sparing surgery performed 77 days (median) after the first cycle (range 56–114 days). Intent to treat analysis showed 16/43 GR (37%). With a median follow-up of 36 months (25–48), the 2 year event-free and overall survival were 74% and 86% respectively. Conclusions: Despite the haematological toxicities, these results compare favorably with other previous induction CT schedules containing MTX in adults. A longer follow-up is required to evaluate the impact of this regimen on overall survival. No significant financial relationships to disclose.

Hyper-alkalinization instead of hyper-hydration for the prevention of high-dose methotrexate (HDMTX) induced nephrotoxicity in osteosarcoma patients

9059 Background: Acute tubulopathy is a severe renal toxicity of HDMTX. To prevent this risk, urine alkalinization is combined with hyper-hydration. However, early hyper-hydration rapidly decreases the plasma-to-tissue concentration gradient of methotrexate (MTX) and might reduce its antitumoral effect. We studied the renal prevention offered by hyper-alkalinization without hyper-hydration. Methods: The dose of HDMTX was 8 (3pts) or 12g/m2 (16pts), administered as a 4-hour infusion. Hypertonic 8.4% sodium bicarbonate was infused prior to HDMTX and once daily for three days. Methotrexatemia was measured at H4 (Cmax), H24, and H48 and H72. Urinary pH was measured on each miction. Creatininemia was assessed on days 1, 3 and 8. Results: Nineteen patients (7 females, 12 males) were entered. Median age: 17 years (range: 15–19). Number of cycles per patient: 16. A total of 304 cycles of HDMTX were evaluable for MTX pharmacokinetics and toxicity. Urinary pH remained constantly higher than 7.5 in all patients. The mean Cmax, H24 and H48 concentrations were 1203 μmol/l, 11.67 μmol/l and 0.43 μmol/l, respectively. In 5 cycles, reversible creatininemia elevation (< 1.5 ULN) was noticed. No episode of acute severe nephrotoxicity was observed. The main toxicity was hypokaliemia from H48. No re-hospitalisation was required. Conclusions: Hyper-alkalinization appears an efficient and reliable method to prevent the acute renal toxicity of HDMTX. No significant financial relationships to disclose.

High-dose methotrexate toxicity in elderly patients with primary central nervous system lymphoma

The dose of high-dose methotrexate (HDMTX) in elderly patients often has to be reduced, resulting in a loss of treatment efficacy. We evaluated HDMTX-related toxicity with special regard to age distribution in patients with primary central nervous system lymphoma (PCNSL) in a phase IV multicenter trial. One hundred and fifty-four patients (median age 61 years; 89 patients >60 years old, 21 patients >70 years old) received 619 HDMTX cycles. Toxicity was evaluated prospectively using the WHO classification. Unless a reduced dose was required after calculating a decreased glomerular filtration rate (GFR), the patients received 4 g/m(2) HDMTX followed by leucovorin rescue. Toxicity was generally mild with toxicities of WHO grade > or =3 usually <10%. The differences in the incidence and severity of toxicity were not statistically significant between patients >60 years and < or =60 years old. The same was true for therapy termination owing to MTX toxicity and for delayed serum MTX clearance. Dose reduction significantly differed between patients < or =60 years and those >60 years old (18% versus 44%; P = 0.001). HDMTX is a safe treatment for PCNSL patients regardless of age, with adherence to dose reduction determined by calculating the GFR before each treatment cycle.

Comparison of high-dose methotrexate (HDMTX) toxicity in elderly and younger patients (pts) with primary central nervous system lymphoma (PCNSL)

8041 Background: A reduced dose of HDMTX is often given to elderly pts because of the risk of toxicity. This may result in loss of treatment efficacy and further prognosis impairment in this poor prognosis population. Methods: HDMTX toxicity was prospectively evaluated in an ongoing randomized multicenter phase IV study in PCNSL pts. In 154 pts, an analysis of toxicity according to the pts' age was performed. Median age was 61 years (yrs). Sixty-five pts were ≤ 60 yrs and had a median Karnofsky performance score (KPS) of 80, 89 pts were > 60 yrs and had a median KPS of 70. HDMTX (4 g/m2 per course) was administered as a 4-hour intravenous (IV) infusion on day 1 every 2 weeks for a maximum of 6 courses and was accompanied by IV hydration, urinary alkalinization, and leucovorin rescue at a dose of 30 mg IV every 6 hours after 24 hours of HDMTX infusion. HDMTX dose reduction was performed according to creatinine clearance values evaluated before each treatment course: the percentage of dose reduction equaled the percentage of creatinine clearance value below 100 ml/min. Results: Toxicity was generally mild to moderate. No statistically significant differences in frequency and severity of toxicity between pts ≤ 60 and > 60 yrs were noted (table). No therapy-related deaths occurred. Dose reduction due to decrease in creatinine clearance was much more frequent in pts > 60 yrs than in those ≤ 60 yrs (43.9 % versus 17.5 %, p = 0.001). Conclusions: HDMTX is safe regardless of age when dose reduction is performed according to creatinine clearance. Dose reduction solely according to age does not appear to be justified. No significant financial relationships to disclose.

High-dose methotrexate in the treatment of adult acute lymphoblastic leukemia.

The application of high-dose treatment elements has an increasing importance in the therapy of acute lymphoblastic leukemia (ALL). High-dose methotrexate (HDMTX) has been introduced in clinical trials more than 20 years ago, since it has several theoretical advantages compared to conventional dose methotrexate. These trials revealed that the efficacy and toxicity of HDMTX depends on features such as dose level, infusion time, combination regimen and schedule of leucovorin rescue. Particularly the application of controlled leucovorin rescue and improved supportive care enabled the application of increasing doses of HDMTX in the treatment of childhood and adult ALL within a variety of schedules and at dose levels mostly ranging between 0.5 g/m2 and 5.0 g/m2. In childhood ALL, first devised to replace CNS irradiation in the prophylaxis of CNS relapse HDMTX has contributed to the reduction of bone marrow relapses particularly in low risk B-lineage ALL. In addition it proved to be an effective therapy element for prophylaxis and treatment of CNS disease. At least in low risk ALL CNS irradiation could be safely replaced by repeated cycles of HDMTX with additional intrathecal therapy. In adult ALL only few of the successful treatment approaches with HDMTX have been investigated up to now. The results indicate that HDMTX has a beneficial effect with regard to overall outcome in adult B-lineage ALL. It provides effective CNS prophylaxis in combination with intrathecal therapy. In mature B-ALL HDMTX proved to be one of the most effective treatment elements and contributed to an impressive improvement of outcome in this subgroup. For T-ALL however sufficient data do not exist either in childhood or in adult ALL. Since HDMTX is an effective treatment element with manageable acute and long-term toxicity, its role in the management of adult ALL should be explored more intensively.

Safety and Efficacy of I‐Leucovorin Rescue Following High‐Dose Methotrexate for Osteosarcoma

High-dose methotrexate with leucovorin rescue (HDMTX-LCV) is an important component of regimens used in the treatment of osteosarcoma. As of this writing the commercially available form of leucovorin is a racemic mixture of d- and l-diastereoisomers; the l-isomer is the active component. This study describes the efficacy and safety of l-leucovorin in HDMTX-LCV regimens. Fifteen patients with osteosarcoma who were enrolled into or treated according to Pediatric Oncology Group protocols 8759 and 8651 received l-leucovorin (7.5 mg every 6 hours) in place of d,l-leucovorin following high-dose methotrexate. Safety data were collected for 1 week after each course or until any toxicities resolved. The mean number of l-leucovorin doses per course was 16.2 and the mean total dose per course was 126 mg. Adverse experiences were generally mild or moderate and occurred in 54 (60%) of 90 courses of l-leucovorin therapy. One l-leucovorin patients, who had inadequate methotrexate rescue, developed severe typhlitis. There were no instances of severe, acute methotrexate toxicity. Myelosuppression was seen but, in general, was not severe. These results support the conclusion that l-leucovorin effectively rescues patients from the toxicity of high-dose methotrexate.

High-dose methotrexate with citrovorum factor rescue and adriamycin in childhood osteogenic sarcoma.

Thirteen children with metastatic osteogenic sarcoma were given high-dose methotrexate (HDMTX) with Citrovorum factor (CF) rescue and adriamycin cyclic chemotherapy. HDMTX (100–750 mg/kg) IV. was infused during 4 hours, followed by CF administration (9 mg P.O. q6h × 12). Two weeks later, adriamycin, 2.5 mg/kg divided into three daily doses (1 mg/kg, 1 mg/kg, and 0.5 mg/kg), was given by I.V. injection. The cycle was repeated every 4 weeks. Of 13 patients treated, 7 had tumor regression for greater than 1 month. In 7/7 patients, the elevated serum alkaline phosphatase levels normalized after treatment, and 5/6 patients had relief of bone pain. HDMTX toxicity included mucositis, leukopenia, thrombocytopenia, transient elevation of SGOT, nausea and vomiting, and radiation pneumonitis in 2 patients who received thoracic irradiation after HDMTX. Responses and symptom-free survival in patients with advanced osteogenic sarcoma suggest that this treatment would be of value as adjuvant therapy in the treatment of primary osteogenic sarcoma in an effort to improve the poor cure rate with surgery alone.