Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma

Abstract Significant advances have been made in the treatment of malignant lymphomas in children; however, approximately 20–30% will have refractory or recurrent disease. These patients are felt to have a relatively poor prognosis primarily because of the comprehensive and intensive nature of their frontline therapies; therefore, they are generally considered for a novel or more aggressive salvage regimen. The purpose of this study is to determine the activity and toxicity profile of the MIED regimen (high-dose methotrexate, ifosfamide, etoposide and dexamethasone) in children with refractory or recurrent non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). From 1991 to 2006, 62 children with refractory/recurrent NHL (n=24) and HL (n=38) were treated with 1 to 6 sequential cycles of MIED (methotrexate, 8 grams/m2 on day 1; ifosfamide, 2 grams/m2 on days 2–4; etoposide, 200 mg/m2 on days 2–4; and dexamethasone, 40 mg/m2 on days 1–4). Children with NHL also received intrathecal MHA (methotrexate, hydrocortisone, and cytarabine at age adjusted dosages) on day 1. Response evaluation was performed after 1 – 2 cycles of MIED. Children with either a PR or CR were considered for an intensification phase with hematopoietic stem cell transplantation (HSCT); patients with HL also received involved-field irradiation. Forty-six (75%) of the 61 evaluable children with refractory or recurrent lymphoma responded to MIED (CR, 23; PR, 23). Among the 24 children with NHL (large cell, 18 [anaplastic large cell, 8; diffuse large B-cell, 3; T-cell large cell, 2; large cell not otherwise specified, 5]; Burkitt, 3; lymphoblastic, 2; other, 1), responses included: CR (n=10), and PR (n=5) for a combined CR+PR rate of 63%. Among the 37 children with HL (nodular sclerosis, n = 29; mixed cellularity, n =4; lymphocyte predominant, n =1; and HL not otherwise specified, n=3) responses included: CR (n=13), and PR (n=18) for a combined CR+PR rate of 84% among 37 evaluable patients. MIED was generally well tolerated (associated with grade IV hematologic toxicity in most cases and frequently associated with mucositis and/or fever with neutropenia). Nineteen of 24 children with NHL and 31 of 37 children with HL received an intensification phase with HSCT support (autologous, 46; allogeneic, 4) at some point following MIED therapy. Nine of 24 children (38%) with NHL are alive and disease-free. Twenty-eight of 37 children (76%) with HL are currently alive (24 disease-free post HSCT). MIED is an active and generally well tolerated regimen for children with refractory or recurrent malignant lymphoma.

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High-Dose Methotrexate, Rituximab, and Temozolomide (MRT) for Patients with Primary CNS Lymphoma (PCNSL).

Blood ◽

10.1182/blood.v114.22.1672.1672 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1672-1672 ◽

Cited By ~ 1

Author(s):

Elizabeth R. Gerstner ◽

Fred H Hochberg ◽

Scott R. Plotkin ◽

April F. Eichler ◽

Tracy T. Batchelor

Keyword(s):

Salvage Therapy ◽

Initial Diagnosis ◽

Induction Treatment ◽

High Dose ◽

High Dose Methotrexate ◽

Newly Diagnosed ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Dose Methotrexate

Abstract Abstract 1672 Poster Board I-698 Introduction PCNSL is a rare form of non-Hodgkin lymphoma. High-dose methotrexate (HD-MTX) is the backbone of therapy but uncertainty remains about what additional chemotherapies should be added to HD-MTX to improve response rates. Methods After receiving IRB consent, we retrospectively evaluated patients with PCNSL treated at our hospital with combination M/R/T at initial diagnosis or at relapse. Patients were treated in 28-day induction cycles as follows: HD-MTX (8g/m2- dose adjusted based on creatinine clearance) on days 1 and 15; rituximab (375 mg/m2) on days 3, 10, 17, and 24; and temozolomide (150-200 mg/m2) on days 7-11. HD-MTX was given every 2 weeks until complete response (CR) and for 2 additional treatments followed by monthly maintenance treatments for 11 months. Rituximab was given weekly for a total of 8 weeks. Temozolomide was continued for 6 months after CR. Brain MRI was done after every other methotrexate treatment to assess response. Results Sixteen patients were treated between February 2006 and August 2009. Ten patients received MRT as first-line therapy at the time of initial diagnosis and 6 received MRT as salvage therapy at first or second recurrence. The median age of newly diagnosed patients was 58 (range 47-76) and of relapsed patients was 60 (range 46-76). CSF cytology was atypical in 5/15 patients who underwent lumbar puncture (4 first-line, 1 relapse). After first-line therapy, there were 9 CRs (median cycles to CR = 3) and 1 PR (patient still receiving induction treatment). After salvage therapy, there were 4 CRs (median cycles to CR = 4) and 2 PRs (both patients died while receiving treatment- 1 from an unrelated myocardial infarction). With a median follow-up of 10.3 months in the first-line group and 7.2 months in the relapse group, only 3 patients have progressed; one of whom had clinical progression after a PR and a second who relapsed in the skin. Treatment was well tolerated with reversible grade 4 transammonitis in 1 patient and grade 3 hematological toxicities in 8 patients. One patient experienced grade 4 thrombocytopenia related to temozolomide requiring dose reduction for subsequent cycles. Conclusions Combination MRT is well tolerated and resulted in a promising early response rate. The median number of cycles needed to achieve a CR for patients with newly diagnosed PCNSL was less than the 6 cycles we have previously reported for HD-MTX monotherapy suggesting that adding rituximab and temozolomide is beneficial to patients. This combination warrants further evaluation in larger scale, prospective studies. Disclosures Off Label Use: temozolomide and rituximab for PCNSL..

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The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphoma

Radiology and Oncology ◽

10.2478/raon-2013-0076 ◽

2014 ◽

Vol 48 (3) ◽

pp. 289-292 ◽

Cited By ~ 7

Author(s):

Nina Erculj ◽

Barbara Faganel Kotnik ◽

Marusa Debeljak ◽

Janez Jazbec ◽

Vita Dolzan

Keyword(s):

T Cell ◽

Malignant Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Wild Type ◽

Non Hodgkin Lymphoma ◽

Dose Methotrexate ◽

Folate Pathway ◽

677T Allele

Abstract Background. We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX) related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL). Patients and methods. In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms. Results. Carriers of at least one MTHFR 677T allele had significantly higher MTX area under the time-concentration curve levels at third MTX cycle (P = 0.003). These patients were also at higher odds of leucopoenia (P = 0.006) or thrombocytopenia (P = 0.041) and had higher number of different HD-MTX-related toxicity (P = 0.035) compared to patients with wild-type genotype. Conclusions. Our results suggest an important role of MTHFR 677C>T polymorphism in the development of HD-MTXrelated toxicity in children with NHL.

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High cut-off dialysis as a salvage therapy option in high-dose methotrexate chemotherapy?

Annals of Hematology ◽

10.1007/s00277-013-1909-8 ◽

2013 ◽

Vol 93 (6) ◽

pp. 1053-1055 ◽

Cited By ~ 3

Author(s):

Anna Bertram ◽

Philipp Ivanyi ◽

Carsten Hafer ◽

Kathrin Matthias ◽

Dietrich Peest ◽

...

Keyword(s):

Salvage Therapy ◽

High Dose ◽

High Dose Methotrexate ◽

Dose Methotrexate ◽

Therapy Option ◽

Methotrexate Chemotherapy

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Association between SLC19A1 gene polymorphism and high dose methotrexate toxicity in childhood acute lymphoblastic leukaemia and non Hodgkin malignant lymphoma: introducing a haplotype based approach

Radiology and Oncology ◽

10.1515/raon-2017-0040 ◽

2017 ◽

Vol 51 (4) ◽

pp. 455-462 ◽

Cited By ~ 4

Author(s):

Barbara Faganel Kotnik ◽

Janez Jazbec ◽

Petra Bohanec Grabar ◽

Cristina Rodriguez-Antona ◽

Vita Dolzan

Keyword(s):

Acute Lymphoblastic Leukaemia ◽

Malignant Lymphoma ◽

Children And Adolescents ◽

Lymphoblastic Leukaemia ◽

High Dose ◽

High Dose Methotrexate ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Additional Information ◽

Dose Methotrexate

Abstract Background We investigated the clinical relevance of SLC 19A1 genetic variability for high dose methotrexate (HD-MTX) related toxicities in children and adolescents with acute lymphoblastic leukaemia (ALL) and non Hodgkin malignant lymphoma (NHML). Patients and methods Eighty-eight children and adolescents with ALL/NHML were investigated for the influence of SLC 19A1 single nucleotide polymorphisms (SNPs) and haplotypes on HD-MTX induced toxicities. Results Patients with rs2838958 TT genotype had higher probability for mucositis development as compared to carriers of at least one rs2838958 C allele (OR 0.226 (0.071–0.725), p < 0.009). Haplotype TGTTCCG (H4) statistically significantly reduced the risk for the occurrence of adverse events during treatment with HD-MTX (OR 0.143 (0.023–0.852), p = 0.030). Conclusions SLC 19A1 SNP and haplotype analysis could provide additional information in a personalized HD-MTX therapy for children with ALL/NHML in order to achieve better treatment outcome. However further studies are needed to validate the results.

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