NK T-Cell lymphoma SMILE (dexamethasone methotrexate iFOSFamide asparaginase etoposide) DISCONTINUED

Treatment schedule summary

Cycle 1 and 2

Drug	Dose	Route	Day
Methotrexate	2,000 mg/m2	IV infusion	1
Calcium folinate (Leucovorin) *	15 mg/m2 every 6 hours	IV infusion	2
Dexamethasone	40 mg ONCE a day	PO	2 to 4
Etoposide **	100 mg/m2	IV infusion	2 to 4
iFOSFamide	1,500 mg/m2	IV infusion	2 to 4
Mesna	300 mg/m2	IV infusion	2 to 4
Mesna	300 mg/m2 at 4 and 8 hours post ifosfamide dose	IV infusion	2 to 4
Filgrastim	5 micrograms/kg	Subcut	6 and continue daily until neutrophil recovery
Asparaginase (colaspase) ***	6,000 International Units/m2	IV infusion	8, 10, 12, 14, 16, 18, 20

* Commence 36 hours after the start of methotrexate infusion and repeat every 6 hours until methotrexate level is less than 0.1 micromol/L

** Etopophos (etoposide phosphate) 113.6 mg is equivalent to etoposide 100 mg. Use actual body weight. Doses in this protocol are expressed as etoposide; however Etopophos (etoposide phosphate) is the preferred formulation.

*** The manufacturers of Leunase^® brand of asparaginase (colaspase) have confirmed that one Kyowa Unit (KU) is equivalent to one International Unit. Alternative formulations and routes of administration may be used depending on local institutional policies. 

It is important to note that there are various formulations of asparaginase available and dosing for each formulation is different. Clinicians should therefore ensure that the dose prescribed is appropriate for the asparaginase product being administered.

Link to asparaginase document.

Frequency: 28 days

Cycles: 2 to 3, patients in complete remission (CR) or partial remission (PR) can continue to receive SMILE up to 6 cycles or undergo a BMT.

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Note:

Patients in interim CR with original disease sites judged to be amenable to irradiation received sandwiched IFRT (Involved-Field Radiation Therapy) before the next treatment when treated on SMILE.^r

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Bibliography

HLH-2004. Hemophagocytic lymphohistiocytosis Study Group, Treatment protocol of the second International HLH study.

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Jaccard, A. and O. Hermine. 2011. "Extranodal natural killer/T-cell lymphoma: advances in the management." Curr Opin Oncol 23(5):429-435.

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Extranodal NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. No therapeutic strategy is currently identified in relapsing patients. We report the results of a French prospective phase II trial of an L-asparaginase-containing regimen in 19 patients with relapsed or refractory disease treated in 13 centers. Eleven patients were in relapse and 8 patients were refractory to their first line of treatment. L-Asparaginase-based treatment yielded objective responses in 14 of the 18 evaluable patients after 3 cycles. Eleven patients entered complete remission (61%), and only 4 of them relapsed. The median overall survival time was 1 year, with a median response duration of 12 months. The main adverse events were hepatitis, cytopenia, and allergy. The absence of antiasparaginase antibodies and the disappearance of Epstein-Barr virus serum DNA were significantly associated with a better outcome. These data confirm the excellent activity of L-asparaginase-containing regimens in extranodal NK/T-cell lymphoma. L-Asparaginase-based treatment should thus be considered for salvage therapy, especially in patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma warrants evaluation in prospective trials. This trial is registered at www.clinicaltrials.gov as #NCT00283985.

Ramsey, L. B., F. M. Balis, M. M. O'Brien, et al. 2018. "Consensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate Clearance." Oncologist 23(1):52-61.

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Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a treatment approved by the Food and Drug Administration for high methotrexate concentrations in the context of kidney dysfunction, but the guidelines for when to use it are unclear. An expert panel was convened to provide specific, expert consensus guidelines for the use of glucarpidase in patients who develop HDMTX-induced nephrotoxicity and delayed methotrexate excretion. The guideline provides recommendations to identify the population of patients who would benefit from glucarpidase rescue by more precisely defining the absolute methotrexate concentrations associated with risk for severe or life-threatening toxicity at several time points after the start of an HDMTX infusion. For an HDMTX infusion </=24 hours, if the 36-hour concentration is above 30 microM, 42-hour concentration is above 10 microM, or 48-hour concentration is above 5 microM and the serum creatinine is significantly elevated relative to the baseline measurement (indicative of HDMTX-induced acute kidney injury), glucarpidase may be indicated. After a 36- to 42-hour HDMTX infusion, glucarpidase may be indicated when the 48-hour methotrexate concentration is above 5 microM. Administration of glucarpidase should optimally occur within 48-60 hours from the start of the HDMTX infusion, because life-threatening toxicities may not be preventable beyond this time point. IMPLICATIONS FOR PRACTICE: Glucarpidase is a rarely used medication that is less effective when given after more than 60 hours of exposure to high-dose methotrexate, so predicting early which patients will need it is imperative. There are no currently available consensus guidelines for the use of this medication. The indication on the label does not give specific methotrexate concentrations above which it should be used. An international group of experts was convened to develop a consensus guideline that was specific and evidence-based to identify the population of patients who would benefit from glucarpidase.

Tse, E. and Y. L. Kwong. 2013. "How I treat NK/T-cell lymphomas." Blood 121(25):4997-5005.

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Natural killer (NK)/T-cell lymphomas and NK-cell leukemias are aggressive malignancies. Occurring worldwide, they show a predilection for Asian and South American populations. Neoplastic cells are surface CD3-, cytoplasmic CD3epsilon+, CD56+, cytotoxic-molecule positive, Epstein-Barr virus (EBV) positive, with germline T-cell receptor gene. Lymphomas occur commonly in the nasal and upper aerodigestive region. Occasional cases present in the skin, salivary gland, testis, and gastrointestinal tract. Rare cases are disseminated with lymphadenopathy, hepatosplenomegaly, and a leukemic phase. Positron emission tomography computed tomography is useful in staging, as lymphomas are 18-fluorodeoxyglucose avid. Quantification of circulating EBV DNA is an accurate biomarker of tumor load. Nasal NK/T-cell lymphomas present mostly with stage I/II disease. Concomitant/sequential chemotherapy and radiotherapy is standard treatment. Radiotherapy alone is inadequate because of high systemic failure rate. For stage III/IV nasal, nonnasal, and disseminated lymphomas, systemic chemotherapy is indicated. Regimens containing l-asparaginase and drugs unaffected by P-glycoprotein are most effective. Hematopoietic stem cell transplantation (HSCT) is not indicated for early-stage nasal lymphomas. HSCT for lymphomas not in remission has poor results. In advanced-stage nasal, nonnasal, disseminated, or relapsed lymphomas, HSCT may be considered when remission is achieved. Prognostic modeling and EBV DNA monitoring may be useful in risk stratification for HSCT.

Yamaguchi, M., Y. L. Kwong, W. S. Kim, et al. 2011. "Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study." J Clin Oncol 29(33):4410-4416.

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PURPOSE: To explore a more effective treatment for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKL), we conducted a phase II study of the steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) regimen. PATIENTS AND METHODS: Patients with newly diagnosed stage IV, relapsed, or refractory disease and a performance status of 0 to 2 were eligible. Two cycles of SMILE chemotherapy were administered as the protocol treatment. The primary end point was the overall response rate (ORR) after the protocol treatment. RESULTS: A total of 38 eligible patients were enrolled. The median age was 47 years (range, 16 to 67 years), and the male:female ratio was 21:17. The disease status was newly diagnosed stage IV in 20 patients, first relapse in 14 patients, and primary refractory in four patients. The eligibility was revised to include lymphocyte counts of 500/muL or more because the first two patients died from infections. No treatment-related deaths were observed after the revision. The ORR and complete response rate after two cycles of SMILE chemotherapy were 79% (90% CI, 65% to 89%) and 45%, respectively. In the 28 patients who completed the protocol treatment, 19 underwent hematopoietic stem-cell transplantation. The 1-year overall survival rate was 55% (95% CI, 38% to 69%). Grade 4 neutropenia was observed in 92% of the patients. The most common grade 3 or 4 nonhematologic complication was infection (61%). CONCLUSION: SMILE chemotherapy is an effective treatment for newly diagnosed stage IV, relapsed or refractory ENKL. Myelosuppression and infection during the treatment should be carefully managed.

Version 8

Date	Summary of changes
04/09/2024	Haematology Reference Committee consensus to discontinue this protocol as native E-coli asparaginase (colaspase) is no longer available. It is the view of the committee that protocols with evidence for pegaspargase use in the trials supporting them  (such as ID 4041 NK T-Cell lymphoma modified SMILE (dexamethasone methotrexate iFOSFamide pegaspargase etoposide) be recommended rather than substituting pegaspargase into native E-coli asparaginase containing protocols.
19/09/2024	Protocol discontinued. Increase to v.8.

Version 7

Date	Summary of changes
20/03/2024	Protocol updated with ADDIKD guideline recommendations. New kidney dosing recommendation table added to dose modification section. Version number changed to V.7.
02/04/2024	Extravasation, tissue or vein injury added to side effects per updates to extravasation document.

Version 6

Date	Summary of changes
04/05/2023	Methotrexate target level updated. Version number changed to v.6
16/06/2023	Reviewed electronically by Haematology Reference Committee. Nil changes. Review in 4 years.

Version 5

Date	Summary of changes
22/09/2020	Biosimilar drug added to clinical information. Version number changed to v.5
08/02/2022	PJP prophylaxis clinical information block updated.
30/03/2022	Protocol electronically reviewed by Haematology reference committee for lymphoma RCM 2021. Link to ID 4041 modified SMILE added. Side effects updated. Review period aligned with modified SMILE, for review in 1 year.

Version 4

Date	Summary of changes
16/04/2020	'Mesna dosing and administration' block added to clinical information. Version number changed to v.4

Version 3

Date	Summary of changes
07/03/2014	New protocol taken to haematology Reference Committee meeting
27/05/2014	Approved and published on eviQ
18/08/2014	Added link to ALLG, ANZCTR and Lymphoma Australia website with statement 'Patients with lymphoma should be considered for inclusion into clinical trials'.
11/09/2015	Reviewed at RCM, no changes, review in 2 years, updated drug costs.
31/05/2017	Transferred to new eviQ website. Version number change to v.3. L- asparaginase (colaspase) changed to asparaginase (colaspase) per TGA update, to align with names used internationally https://www.tga.gov.au/updating-medicine-ingredient-names-list-affected-ingredients#active
25/05/2018	Reviewed by Haematology Reference Committee with no significant changes, review in 2 years. Treatment schedule changed from 'Cycle 1 to 3' to 'Cycle 1 to 2' to align with eviQ standard of stating the minimum number of cycles which may be given.
25/10/2018	Link added to high dose methotrexate-induced toxicity document in clinical information.
13/09/2019	Reviewed by Haematology Reference Committee, no changes made. Review in 2 years.
10/10/2019	Clinical information updated with PBS expanded indications for G-CSF.