What Is Lomustine? FDA Approval, Licensing in Turkey, and Reimbursement
| Active ingredient | Lomustine (CCNU) |
| Brand name | Gleostine (USA); no brand name is licensed in Turkey |
| Class | Nitrosourea-derived alkylating agent |
| Category | Antineoplastic agent (conventional cytotoxic chemotherapy) |
| Route of administration | Oral (capsule) |
| Dosing frequency | Single dose, once every 6 weeks |
| Approved cancer indications | Primary/metastatic brain tumors (after surgery/radiotherapy) · Hodgkin lymphoma (in combination, after progression on initial chemotherapy) |
| FDA-approved | Yes — first approval in 1976 (CeeNU); the current brand, Gleostine, has been marketed since 2013 |
| Drugs commonly used in combination | Temozolomide (in MGMT-methylated glioblastoma) · procarbazine + vincristine (PCV regimen) · bevacizumab (recurrent glioblastoma) |
| Manufacturer | NextSource Biotechnology, LLC (Gleostine brand) |
| Turkish Ministry of Health license | NONE |
| SGK reimbursement | Subject to the TEB overseas drug procurement process and relevant medical report requirements |
| Access in Turkey | Turkish Pharmacists' Association (TEB) active overseas drug list can be used to obtain it |
| Half-life | 16–48 hours for metabolites |
Lomustine is one of the oldest drugs in oncology—its first FDA approval dates back to 1976. Although developed approximately fifty years ago, it remains among the standard treatment options for recurrent glioblastoma and certain brain tumors , because one particular property sets it apart: its ability to cross the blood-brain barrier effectively.
This monograph examines in detail how lomustine works, the tumors in which it is used, what recent clinical research (particularly the phase 3 STELLAR study published in 2025) shows, its dosing and safety profile, and the access pathway in Turkey.
Lomustine is a nitrosourea derivative—a member of a conventional chemotherapy class that damages DNA through alkylation. However, two properties distinguish lomustine from other alkylating agents: its high lipid solubility enables it to cross the blood-brain barrier effectively, and, in addition to damaging DNA, it also carbamoylates cellular proteins, providing a second mechanism of action.
Lomustine is therefore one of the few cytotoxic agents that can reach meaningful drug concentrations in brain tissue , which most chemotherapy drugs cannot reach effectively.
- Chemical structure: 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; a yellow powder that is very slightly soluble in water and soluble in alcohol and low-concentration ethanol.
- DNA damage: The chloroethyl group leads to the formation of O6-chloroethylguanine at guanine bases; this develops into permanent cross-links between DNA strands, halting replication and transcription.
- Carbamoylation: This secondary mechanism, characteristic of nitrosoureas, modifies amino acids in cellular proteins and also impairs the function of certain repair enzymes.
- Tissue distribution: Radioactivity levels in cerebrospinal fluid, relative to simultaneous plasma levels, can reach 50% or more —a relatively rare property among orally administered chemotherapy agents.
| Date | Development |
|---|---|
| 1976 | Lomustine received FDA approval under the CeeNU brand for brain tumors and Hodgkin lymphoma (Bristol-Myers Squibb). |
| 2013 | The manufacturer withdrew CeeNU from the market; a short-term supply shortage followed. |
| 2013 | NextSource Biotechnology launched Gleostine for the same indications; it is the only FDA-approved lomustine product today. |
| 2016 | Prescribing information was updated: boxed warnings (delayed myelosuppression, overdose risk) were clarified, and dose rounding was reduced to 5 mg. |
| 2019 | The CeTeG/NOA-09 (Lancet) and REGOMA (Lancet Oncology) studies were published, reinforcing lomustine's position in contemporary comparisons. |
| 2025 | Results of the phase 3 STELLAR study (JCO) showed a survival advantage for eflornithine + lomustine in recurrent grade 3 IDH-mutant astrocytoma. |
Although lomustine is a fifty-year-old drug, its place in research continues to be actively redefined. STELLAR is a study in patients with recurrent grade 3 IDH-mutant astrocytoma ; this randomized phase 3 study tested how adding eflornithine (an oral ornithine decarboxylase inhibitor) affected survival compared with lomustine monotherapy.
In the prespecified subgroup analysis (n=194), eflornithine + lomustine increased median overall survival to 34.9 months , while median survival with lomustine monotherapy remained 23.5 months (HR 0.64; log-rank p=0.016). Benefit was seen only in IDH-mutant grade 3 tumors; no significant difference was found in grade 4 tumors (glioblastoma). This shows that lomustine's efficacy varies according to tumor biology.
| Study | Patient group | Comparison | Main result |
|---|---|---|---|
| STELLAR phase 3 · n=194 (subgroup) |
Recurrent grade 3 IDH-mutant astrocytoma, after RT+TMZ | Eflornithine + lomustine vs lomustine alone | OS advantage: 34.9 vs 23.5 months (HR 0.64; p=0.016). PFS also approximately doubled. No benefit was shown in grade 4 tumors (glioblastoma). |
| CeTeG/NOA-09 phase 3 · n=141 |
Newly diagnosed, MGMT-methylated glioblastoma | Lomustine + temozolomide vs temozolomide alone | Median OS was 48.1 vs 31.4 months (HR 0.60; p=0.049). There was no difference in PFS. Grade ≥3 adverse events: 59% vs 51%. Results should be interpreted cautiously because of the study's small sample size. |
| REGOMA phase 2 · n=119 |
Recurrent glioblastoma, after RT+TMZ | Regorafenib vs lomustine | An OS advantage was shown in the regorafenib arm (7.4 vs 5.6 months; HR 0.50; p=0.0009). Although this result supported regorafenib, lomustine served as the standard comparator in this study. |
| LEGATO / EORTC-2227-BTG phase 3 · ongoing |
First progression in glioblastoma | Lomustine + reirradiation vs lomustine alone | Enrollment is actively ongoing at 33 centers in Europe; results have not yet been published. |
Lomustine offers a limited survival benefit when used alone; however, with appropriate patient selection (MGMT methylation, IDH mutation status) and the right combination (temozolomide, eflornithine), it can deliver meaningful survival gains. This is a good example of how a fifty-year-old molecule can be adapted to modern biomarker-based oncology.
Lomustine's toxic effect on bone marrow is delayed: it develops 4–6 weeks after the dose and lasts 1–2 weeks. The next dose therefore cannot be given before the previous dose's full effect has been observed; otherwise, there is a risk of cumulative and unpredictable myelosuppression. For this reason, the prescribing information includes a specific boxed warning: "prescribe only one dose at a time and dispense only enough capsules for one dose" .
- The standard dose is 130 mg/m² as a single oral dose once every 6 weeks , rounded to the nearest 5 mg. In patients with suppressed bone marrow function, the dose is reduced to 100 mg/m².
- The dose is adjusted according to the previous dose's nadir blood counts: no change is made if leukocytes are ≥4000/mm³ and platelets are ≥100,000/mm³; at lower counts, the dose is reduced by 50–70%.
- Capsules are available in 10 mg, 40 mg, and 100 mg strengths, distinguished by color; a single dose may include capsules of more than one strength.
- The pharmacist and physician must specifically emphasize that the patient should receive only enough capsules for one dose —the entire box must not be dispensed.
- Capsules must not be broken; in the event of skin contact, the affected area should be washed immediately and thoroughly (cytotoxic drug safety precautions).
Absorption: Rapidly absorbed after oral administration; studies using radiolabeled lomustine have demonstrated high absorption.
Distribution: Because of its high lipid solubility and low ionization at physiological pH, it crosses the blood-brain barrier effectively. Radioactivity levels in cerebrospinal fluid can reach 50% or more of simultaneous plasma levels.
Metabolism: The metabolic pathways involved in elimination have not been fully characterized.
Excretion: In studies using radiolabeled lomustine at doses of 30–100 mg/m², approximately half the administered radioactivity was excreted in the urine as degradation products within the first 24 hours. The serum half-life of metabolites ranges from 16 hours to 48 hours . The effects of age, sex, race, or renal/hepatic impairment on pharmacokinetics are unknown.
| Capsule strength | Color | NDC (example) |
|---|---|---|
| 5 mg | Yellow/yellow | 58181-3043-5 |
| 10 mg | White/white | 58181-3040-5 |
| 40 mg | White/moss green | 58181-3041-5 |
| 100 mg | Moss green/moss green | 58181-3042-5 |
- When lomustine is used with other myelosuppressive drugs (e.g., other chemotherapy agents), the dose should be reduced accordingly; the risk of cumulative bone marrow toxicity increases.
- Live vaccines are generally not recommended during chemotherapy because of immunosuppression.
The current FDA prescribing information does not formally list any drug interactions. However, historical observations in the literature suggest that certain agents, such as cimetidine , may increase lomustine-related bone marrow toxicity; additional caution and close blood count monitoring are sensible when these drugs are used together.
- Delayed myelosuppression: The most important and dose-limiting toxicity; it occurs 4–6 weeks after dosing and lasts 1–2 weeks. Thrombocytopenia is generally more severe than leukopenia. Severity and duration increase with cumulative doses.
- Gastrointestinal: Nausea, vomiting, stomatitis—frequently reported adverse effects that are generally manageable in severity.
- Pulmonary toxicity: Pulmonary infiltration and/or fibrosis; pulmonary function testing is recommended before treatment and at frequent intervals. Risk is increased in patients whose baseline FVC or DLCO is below 70% of the predicted value . It usually occurs 6 months or more after treatment begins, when the cumulative dose exceeds 1100 mg/m² .
- Secondary malignancy: Acute leukemia and myelodysplasia have been reported with long-term use.
- Hepatotoxicity: Elevated transaminases, alkaline phosphatase, and bilirubin may occur.
- Nephrotoxicity: Progressive renal failure accompanied by a reduction in kidney size has been reported.
- Neurological/ophthalmological: Disorientation, lethargy, ataxia, dysarthria; optic atrophy, visual impairment, and blindness (rare).
- Alopecia has been reported.
- Risk of fatal overdose: Giving/taking more than one dose may cause fatal toxicity. The physician and pharmacist must specifically emphasize that only a single dose is to be taken every 6 weeks.
- Blood count monitoring: Complete blood counts should be obtained weekly for at least 6 weeks after each dose; the next dose should not be given until leukocyte and platelet counts have recovered adequately.
- Pulmonary function monitoring: Pulmonary function testing before treatment and at frequent intervals; in patients diagnosed with pulmonary fibrosis, treatment is permanently discontinued.
- Liver and kidney function should be monitored regularly.
- Pregnancy and fertility: Teratogenic and embryotoxic effects have been demonstrated in animal studies. Women must use effective contraception during treatment and for 2 weeks after the last dose, while men with female partners must do so for 3.5–4 months after the last dose. Breastfeeding is not recommended. Reduced fertility has been reported.
MGMT (O6-methylguanine-DNA methyltransferase) is a repair enzyme that can prevent DNA cross-link formation by repairing the O6-chloroethylguanine damage caused by lomustine. If the promoter region of the MGMT gene in the tumor is methylated , this repair enzyme is silenced and response to alkylating agents such as lomustine/temozolomide increases. This is precisely the scientific basis for restricting enrollment in CeTeG/NOA-09 to patients with MGMT-methylated tumors.
Other reported resistance mechanisms include reduced cellular uptake of lomustine, increased glutathione levels (which neutralize the alkylating effect), and increased activity of other DNA repair enzymes such as glutathione-S-transferase.
Licensing: Lomustine has not been licensed by the Turkish Ministry of Health; it has no licensed brand name in Turkey.
Access: Lomustine is on the Turkish Pharmacists' Association (TEB) active overseas drug list and can be obtained through TEB and delivered to patients. This is a more institutionalized mechanism than the individual "off-label approval" process seen with certain unlicensed new biological drugs.
Reimbursement: SGK reimbursement depends on the overseas drug procurement process and relevant oncology board report requirements; the current status should be confirmed with the appropriate unit at the treatment center.
- Physician's prescription. The patient's treating oncology/neuro-oncology specialist issues a prescription documenting the diagnosis and treatment rationale.
- Application to TEB. The prescription is submitted to the Turkish Pharmacists' Association's overseas drug procurement unit; because lomustine is on its active list, the process is generally more standardized.
- Procurement and delivery. The drug is imported and delivered to the patient or treatment center.
- Reimbursement assessment. Payment under SGK is assessed separately according to the relevant Health Implementation Communiqué (SUT) provisions and oncology board report requirements.
This process is subject to regulations and may change over time. For the current procedure, the relevant unit at the treating center should be informed.
Who Is This Drug For? Patients with primary/metastatic brain tumors after surgery and/or radiotherapy, and patients with Hodgkin lymphoma unresponsive to initial chemotherapy.
How Is It Taken? It is taken orally as a single dose once every 6 weeks . The dose may require more than one capsule and may include capsules of different colors—follow your pharmacist's instructions exactly. Never take more than the prescribed dose and do not keep extra capsules; overdose can be fatal.
What Should You Watch For? Your blood counts reach their lowest level 4–6 weeks after the dose. During this period, report fever, unusual bleeding or bruising, or severe fatigue to your healthcare team immediately. New or worsening cough, chest pain, or shortness of breath should also be reported.
How Is It Obtained in Turkey? Because it is not licensed in Turkey, it is supplied through the Turkish Pharmacists' Association's overseas drug procurement process with your physician's prescription.
Even in the era of modern targeted therapies and immunotherapies, lomustine retains its place as one of the few "old" chemotherapy agents still in use. The main reason is simple but powerful: it is among the few cytotoxic drugs that can cross the blood-brain barrier effectively. Because of this property, even fifty years later, its use for recurrent glioblastoma and grade 3 astrocytoma remains a subject of current research .
STELLAR (n=194, subgroup): eflornithine + lomustine increased OS from 23.5 to 34.9 months in recurrent grade 3 IDH-mutant astrocytoma (HR 0.64; p=0.016); no benefit in grade 4 tumors. CeTeG/NOA-09 (n=141): lomustine+temozolomide increased OS from 31.4 to 48.1 months in MGMT-methylated glioblastoma (HR 0.60; p=0.049)—an impressive finding, but limited by the small sample. REGOMA (n=119): lomustine was used as the standard comparator against regorafenib (OS 5.6 vs 7.4 months), illustrating lomustine's currently limited efficacy in recurrent glioblastoma.
Lomustine monotherapy offers a limited survival benefit in recurrent glioblastoma (as reflected by the median OS of 5.6 months in REGOMA). Delayed and cumulative myelosuppression severely restricts dosing flexibility and requires strict prescribing discipline because of overdose risk. CeTeG/NOA-09's small sample size (n=141) calls for cautious interpretation of its results. Risks of pulmonary fibrosis and secondary malignancy must not be overlooked, particularly with prolonged/cumulative use. A limitation specific to Turkey is that the drug is not licensed there.
When prescribing lomustine, knowledge of MGMT methylation and IDH mutation status plays a key role in identifying patients who may benefit more from combination therapy (with temozolomide or eflornithine). Strict adherence to the single-dose/every-6-weeks schedule and weekly blood count monitoring are the most important tools for managing fatal overdose and cumulative toxicity risks. In Turkey, access follows a relatively more predictable process because of TEB's active overseas drug list; however, SGK reimbursement conditions should be confirmed at each center.
The LEGATO study results will show whether lomustine + reirradiation can establish a new standard in recurrent glioblastoma. Can the eflornithine benefit seen in STELLAR be extended to tumor subtypes other than grade 3? Will CeTeG/NOA-09's findings be confirmed in a larger validation study? Could lomustine provide additional benefit when combined with new targeted agents, such as antiangiogenic agents or immunotherapy combinations?
- This document does not provide dose-adjustment advice and does not recommend any treatment regimen.
- The drug is not licensed in Turkey; FDA approval does not mean automatic access in Turkey.
- Overdose can be fatal; patients must never be given capsules for more than one dose.
- CeTeG/NOA-09 and the STELLAR subgroup data have small sample sizes; results should be interpreted cautiously.
- The decision to use the drug rests solely with the oncology/neuro-oncology specialist who knows the patient.
- GLEOSTINE (lomustine) Prescribing Information, NextSource Biotechnology, LLC, revised 1/2016. FDA access: accessdata.fda.gov (017588s042lbl).
- Herrlinger U, Tzaridis T, Mack F, et al. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial. Lancet. 2019;393(10172):678-688.
- Lombardi G, De Salvo GL, Brandes AA, et al. Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a randomised, controlled, phase 2 trial. Lancet Oncol. 2019;20(1):110-119.
- Coleman H, Lombardi G, Wong E, et al. STELLAR: Phase III, Randomized, Open-Label Study of Eflornithine Plus Lomustine Versus Lomustine Alone in Patients With Recurrent Grade 3 Astrocytoma. J Clin Oncol. 2025.
- Preusser M, Kazda T, Le Rhun E, et al. Lomustine with or without reirradiation for first progression of glioblastoma, LEGATO, EORTC-2227-BTG: study protocol for a randomized phase III study. Trials. 2024;25(1):366.
- NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers, current version.
Editor's note: This monograph is for general information only; it is not medical advice, a diagnosis, or a treatment recommendation, and does not promote any product. All data presented have been verified against primary sources and conveyed without direct quotation. This document deliberately does not include dose-adjustment advice; dosing information is summarized from the FDA prescribing information solely for general educational purposes, and treatment decisions are the sole responsibility of the treating physician. Lomustine has not been licensed in Turkey by the Turkish Ministry of Health; FDA approval does not mean that a drug is licensed, accessible, or reimbursed in Turkey, and overseas procurement/reimbursement procedures may change according to regulations. Lomustine overdose can be fatal; the drug must never be taken at more than the prescribed dose, and extra capsules must not be kept. Reported clinical trial results, particularly the CeTeG/NOA-09 and STELLAR subgroup analyses, should be interpreted cautiously because of their small sample sizes. Do not stop or change any medication without consulting your physician; for drug procurement, contact only your treating oncologist. Consult a physician who knows you for every decision about your health.
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