MBCL-15. TOXICITY PROFILE AND RESPONSE TO HIGH DOSE METHOTREXATE, BEVACIZUMAB, AND TEMOZOLOMIDE CHEMOTHERAPY REGIMEN IN CHILDREN WITH RECURRENT MALIGNANT PEDIATRIC BRAIN TUMORS: SINGLE INSTITUTION EXPERIENCE

Background. Dose-dependent response makes certain pediatric brain tumors appropriate targets for high-dose chemotherapy with autologous hematopoietic stem-cell rescue (HDCT-AHSCR).Methods. The clinical outcomes and toxicities were analyzed retrospectively for 18 consecutive patients ≤19 y/o treated with HDCT-AHSCR at UCLA (1999–2009).Results. Patients' median age was 2.3 years. Fourteen had primary and 4 recurrent tumors: 12 neural/embryonal (7 medulloblastomas, 4 primitive neuroectodermal tumors, and a pineoblastoma), 3 glial/mixed, and 3 germ cell tumors. Eight patients had initial gross-total and seven subtotal resections. HDCT mostly consisted of carboplatin and/or thiotepa ± etoposide (n=16). Nine patients underwent a single AHSCR and nine ≥3 tandems. Three-year progression-free and overall survival probabilities were 60.5% ± 16 and 69.3% ± 11.5. Ten patients with pre-AHSCR complete remissions were alive/disease-free, whereas 5 of 8 with measurable disease were deceased (median followup: 2.3 yrs). Nine of 13 survivors avoided radiation. Single AHSCR regimens had greater toxicity than ≥3 AHSCR (P<.01).Conclusion. HDCT-AHSCR has a definitive, though limited role for selected pediatric brain tumors with poor prognosis and pretransplant complete/partial remissions.

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A prospective phase II trial of response adapted whole brain radiotherapy after high dose methotrexate based chemotherapy in patients with newly diagnosed primary central nervous system lymphoma-analysis of acute toxicity profile and early clinical outcome

Journal of Neuro-Oncology ◽

10.1007/s11060-018-2856-y ◽

2018 ◽

Vol 139 (1) ◽

pp. 153-166 ◽

Cited By ~ 6

Author(s):

Narayan Adhikari ◽

Ahitagni Biswas ◽

Ajay Gogia ◽

Ranjit Kumar Sahoo ◽

Ajay Garg ◽

...

Keyword(s):

Phase Ii Trial ◽

Central Nervous System Lymphoma ◽

Whole Brain Radiotherapy ◽

High Dose ◽

High Dose Methotrexate ◽

Toxicity Profile ◽

Newly Diagnosed ◽

Brain Radiotherapy ◽

Dose Methotrexate ◽

Prospective Phase

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Predictors of Delayed Clearance and Toxicities from High Dose Methotrexate in Patients Receiving Hypercvad Regimen for Treatment of Lymphoid Malignancies

Blood ◽

10.1182/blood.v128.22.1630.1630 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1630-1630

Author(s):

Hong Yen Ng ◽

Pei Shi Ong ◽

Xue Ming Loy ◽

Yufei Chen ◽

Yeow Tee Goh

Keyword(s):

Sample Size ◽

Small Sample ◽

High Dose ◽

High Dose Methotrexate ◽

Toxicity Profile ◽

Clinical Factors ◽

Lymphoid Malignancies ◽

Dose Methotrexate ◽

Slco1b1 Gene ◽

Number Of Treatment

Abstract Introduction: High dose Methotrexate (HDMTX) has been the backbone of chemotherapeutic regimens used for the treatment of lymphoid malignancies. Altered disposition of MTX may result in increased systemic exposure accompanied by severe adverse effects and organ toxicities. Diversity in toxicity profile has been shown to be associated with various clinical factors as well as genetic polymorphisms. In particular, single nucleotide polymorphisms (SNPs) in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene especially rs4149056 and rs2306283 had been previously reported to be significantly associated with MTX concentration at 24 hours post-infusion, MTX AUC from 0-48 hours, MTX clearance and toxicities in the Caucasian pediatric population. Aim: This study aimed to characterize clearance and toxicity profile [in particular acute kidney injury (AKI) and hepatotoxicity]; and identify clinical and genetic covariates associated with clearance and toxicities of HDMTX in patients receiving HyperCVAD-B regimen for treatment of lymphoid malignancies in the local setting. Methods: This single-centered, retrospective study included all treatment-naïve patients of Asian descent who received HDMTX as part of the HyperCVAD-B regimen for treatment of lymphoid malignancies from January 2008 to December 2015 in Department of Hematology, Singapore General Hospital. Pertinent clinical data including baseline demographics, disease characteristics, treatment details, plasma MTX levels, and treatment outcomes were extracted from case notes and electronic records onto a standardized data collection form. Association between toxicities parameters and MTX levels were analyzed. Genotyping for two SNPs in the SLCO1B1 gene namely, rs2306283 and rs4146056 was using blood samples obtained from the Hematology Department Tissue Repository. Primary endpoint was incidence of delayed clearance and toxicities of HDMTX in the study population. Secondary endpoints included clinical factors and genetic covariates associated with reduced MTX clearance and toxicities. Results: A total of 102 patients (215 treatment cycles) were included, with each patient receiving median of 2 cycles (range, 1 to 6). Median age was 45 years (range, 18 - 69), and 58 (56.9%) were male. Eighty-seven patients were diagnosed with acute lymphoblastic leukemia (ALL), whereas 12 patients had lymphoma. Sixty-one patients (59.8%) were found to have at least 1 episode of delayed clearance, occurring in 89 (41.4%) treatment cycles. Median time to MTX clearance was significantly longer in patients with delayed clearance at 69.8 hours (range, 4.5-277.2) as compared to 41 hours (range, 0 - 86.3 hours), p<0.001. Approximately 25% and 47% of the patients developed AKI and hepatotoxicity attributable to MTX, respectively. A significant association between delayed clearance and occurrence of AKI was observed, with 24% of patients with delayed clearance developing AKI vs 2% in those without delayed clearance, p<0.001. Number of treatment cycles [odds ratio (OR) = 2, 95% confidence interval (CI) 1.3 - 3.1, p = 0.002]; and age ≥ 40 (OR 3.7, 95% CI 1.4 - 9.6, p = 0.008) were found to be associated with delayed clearance. Occurrence of delayed clearance (OR = 29, 95% CI = 3.7 - 228, p = 0.001), and baseline hepatic impairment (OR = 9.5, 95% CI = 2 - 45, p = 0.005) were found to predict for AKI and hepatotoxicity, respectively. Genotyping for SLCO1B1 rs2306283 and rs4146056 was carried out for 39 patients with samples available in the repository. Frequencies and outcomes were shown in Table 1 and Table 2, respectively. Due to the small sample size, no definitive correlations between specific genotypes and clearance and outcomes could be elucidated. Conclusion: Delayed clearance of HDMTX occurred in a substantial proportion of patients at approximately 60%, which was in turn associated with occurrence of AKI. Risk of delayed clearance seemed to increase with age (≥ 40) and number of treatment cycles. This underscores the need for more effective strategies to facilitate clearance of HDMTX especially in patients with identified risk factors. Larger sample size would be essential to determine associations between genotypes and clearance and toxicities. Disclosures No relevant conflicts of interest to declare.

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Newly diagnosed high-risk malignant brain tumors with leptomeningeal dissemination in young children: A final update on Head Start II Regimen A2 intensified with high-dose methotrexate

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.9552 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 9552-9552

Author(s):

S. Chi ◽

S. Gardner ◽

L. Y. Ji ◽

R. Sposto ◽

G. Dhall ◽

...

Keyword(s):

High Risk ◽

Head Start ◽

Young Children ◽

Brain Tumors ◽

Response Rate ◽

High Dose ◽

High Dose Methotrexate ◽

Leptomeningeal Dissemination ◽

Newly Diagnosed ◽

Dose Methotrexate

9552 Background: The prognosis for young children with newly diagnosed malignant brain tumors with leptomeningeal dissemination remains poor. From Jan 1997 to Mar 2003, “Head Start II” Regimen A2, intensified with high-dose methotrexate, was offered to this high-risk population. Methods: Eligibility: patients < 10 yrs of age; confirmed diagnosis of medulloblastoma (MB), primitive neuroectodermal tumor (PNET), ependymoma and choroid plexus carcinoma (CPC); and high-risk status as determined by neuroaxis dissemination. Patients with atypical teratoid/rhabdoid tumor (ATRT), regardless of stage, were also eligible. Treatment: 5 cycles of vincristine (0.05 mg/kg/week × 3 doses), cisplatin (3.5 mg/kg), etoposide (4 mg/kg/day × 2 days), cyclophosphamide (65 mg/kg/day × 2 days), and methotrexate (400 mg/kg) with leucovorin. Children without progressive disease (PD) by the end of induction underwent a single consolidation cycle (carboplatin, etoposide, thiotepa) with autologous stem cell rescue. Reduced dose RT (2340cGy CSI and focal boost) was reserved for any with residual disease at the end of induction or for the older patient (>6 yrs of age). Results: 40 patients were enrolled (MB, 22; PNET, 6; ependymoma, 5; AT/RT, 6; CPC, 1), med age at diagnosis 38 mos (range 5 to 119 mos). Significant toxicities of this intensified regimen included GI toxicities and infections. Among the entire cohort, there were 26 CR, 6 PR, 2 with stable disease and 4 with PD (and 2 toxic deaths), for a CR +PR response rate of 82%. For disseminated MB (4 M1; 2 M2; 16 M3), the CR rate alone is 77% (17/22). The 5-year EFS and OS for disseminated MB are 45% (95% CI, 24 % to 64%) and 54% (95% CI, 31% to 72%), respectively. Of note, 6/12 MB survivors (all M3) did not receive RT and all are NED >5 years from diagnosis. In addition, there are 3 AT/RT survivors, 12, 54 and 66 mos post-diagnosis who did not receive RT. Conclusions: This intensified regimen is feasible and tolerable. For patients with disseminated MB, the majority of whom had M3 disease at diagnosis, the impressive response rate and outcomes suggest that the addition of methotrexate is justified for future studies. Long- term neuropsychological outcomes are being studied at this time. No significant financial relationships to disclose.

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High-dose methotrexate in the treatment of acute lymphoblastic leukemia: Toxicity profile and comparison of tolerability betwen two dosage schedules.

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.15_suppl.9573 ◽

2010 ◽

Vol 28 (15_suppl) ◽

pp. 9573-9573

Author(s):

A. R. Warrier ◽

R. Rejiv ◽

D. Biswajit ◽

S. G. Ramanan ◽

T. G. Sagar

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

High Dose ◽

High Dose Methotrexate ◽

Toxicity Profile ◽

Dose Methotrexate

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A single-institution experience with the hyper-CVAD regimen in aggressive NHL.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18510 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18510-e18510

Author(s):

Mariam Younas ◽

Stephanie A. Gregory ◽

Ahmad Jajeh ◽

Melissa L. Larson ◽

Taha Al-Rifai

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Hematological Malignancies ◽

Chemotherapy Regimen ◽

Lymphoblastic Leukemia ◽

Response To Therapy ◽

High Dose ◽

Single Institution ◽

Dose Methotrexate ◽

40Mg Daily ◽

Age Over 60

e18510 Background: Hyper-CVAD (± rituximab) is a chemotherapy regimen designed as a treatment for aggressive hematological malignancies. It consists of 8 cycles. Cycle 1, 3, 5, 7 (3-4 weeks/cycle) includes cyclophosphamide 300mg/m2 IV over 2 hours (hrs) every 12 hrs for 6 doses on day 1-3 + Mesna 600mg/m2 per day continuous IV on days 1-3 to start 1 hr before cyclophosphamide till 12 hrs after completion of cyclophosphamide + vincristine 2mg IV on days 4 and 11 + doxorubicin 50mg/m2 IV over 24 hrs on Day 4 + dexamethasone 40mg daily orally on days 1-4 and days 11-14. Cycle 2, 4, 6, 8 (3-4 weeks/cycle) consist of high dose methotrexate (MTX) (200mg/m2) IV over 2 hrs followed by 800mg/m2 continuous IV infusion over 22 hrs on day 1 + cytarabine 3gm/m2 (1gm/m2 for patient age over 60 years old) IV over 2 hrs every 12 hrs for doses on days 2 and 3 + leucovorin 50mg IV every 6 hrs starting 12 hrs after completion of MTX till MTX level < 0.05µM. Hyper-CVAD is a short intensified regimen given over eight months compared to known therapy for ALL and Burkitt lymphoma. Methods: Retrospective review of all cases of acute lymphoblastic leukemia/lymphoma and Burkitt’s lymphoma between 2000 and 2012 was done. It included all patients and evaluated response to therapy including Hyper-CVAD. Results: A total of 79 patients with aggressive acute lymphoblastic leukemia/lymphoma and Burkitt’s NHL were analyzed. Mean age 39 years (range 15-75 years). All patients were admitted at least twice with febrile neutropenia. Prolonged cytopenias were observed in more than 50% of patients. Conclusions: Hyper-CVAD is an intense regimen that produces high rates of clinical remission in less than 8 months of therapy compared to established regimen for aggressive hematological malignancies. [Table: see text]

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