Procarbazine
| Evidence Level: L3 | Predicted Indications: 5 |
Table of Contents
Procarbazine: From Hodgkin Lymphoma to Follicular Lymphoma
One-Sentence Summary
Procarbazine is an oral alkylating-type chemotherapy agent, originally used to treat Hodgkin lymphoma. The TxGNN model predicts it may be effective for follicular lymphoma. Direct support is limited: 2 related clinical trials (neither of them a clear test of procarbazine) and 12 publications, of which only a few directly address procarbazine.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Hodgkin lymphoma (including classic Hodgkin lymphoma and related subtypes) |
| Predicted New Indication | Follicular lymphoma |
| TxGNN Prediction Score | 99.46% |
| Evidence Level | L3 |
| US Market Status | Cancelled only (no active license) |
| Number of NDAs | 1 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available. Based on known information, procarbazine is an oral alkylating-type agent with established activity in lymphoid malignancies, and its efficacy in Hodgkin lymphoma has been proven. Mechanistically, it may be applicable to follicular lymphoma.
Both Hodgkin lymphoma and follicular lymphoma are lymphoid cancers, so shared lymphoma biology makes activity plausible. Procarbazine was also used in non-Hodgkin lymphoma regimens before CHOP became standard. A 2006 report describes two patients with relapsed or refractory follicular lymphoma who achieved a complete and durable remission with prolonged daily procarbazine. The low-dose oral PEP-C regimen, a metronomic combination, has also been studied in relapsed or refractory lymphoma.
This link rests on shared disease biology and small case-level evidence, not on a confirmed mechanism.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00003113 | Phase 2 | Terminated | 6 | Oral combination chemotherapy plus G-CSF in elderly patients with intermediate- and high-grade non-Hodgkin lymphoma. The regimen likely contains procarbazine, but this is inferred and should be verified. Terminated early, so there are no interpretable efficacy data. |
| NCT00577993 | Phase 3 | Completed | 210 | Fludarabine, mitoxantrone and dexamethasone plus rituximab in stage IV indolent lymphoma, comparing concurrent versus sequential rituximab. Procarbazine is not named, so it is relevant to the disease but not to the drug. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 16690522 | 2006 | Review / case report | Leukemia & Lymphoma | Two patients with relapsed or refractory follicular lymphoma achieved complete, durable remission on prolonged daily procarbazine |
| 22507790 | 2012 | Cohort | Hematology | PEP-C low-dose oral metronomic chemotherapy regimen for refractory or relapsed lymphoma |
| 11672513 | 2001 | RCT | J Hematother Stem Cell Res | Chemotherapy plus interferon-alpha2b versus chemotherapy alone in follicular lymphoma (procarbazine involvement not confirmed) |
| 1702144 | 1991 | Randomized trial | J Clin Oncol | ProMACE-CytaBOM was superior to ProMACE-MOPP in advanced diffuse aggressive lymphoma. Procarbazine appears in the comparator regimens, and the study population is not follicular lymphoma. |
| 16230674 | 2005 | Review | J Clin Oncol | Newer treatment options have changed survival in follicular lymphoma (background context) |
| 6370065 | 1984 | Observational | Ann Intern Med | Prolonged initial remission in nodular mixed lymphoma treated at the NCI (background context) |
| 6366124 | 1983 | Review | J Clin Oncol | Histologic conversion in non-Hodgkin lymphomas (background context) |
| 8426197 | 1993 | Cohort | J Clin Oncol | Clinical features and prognosis of follicular large-cell lymphoma (background context) |
The remaining retrieved papers cover mitoxantrone, fludarabine myelotoxicity, localized aggressive lymphoma and grade 3 gliomas. They are not directly relevant to procarbazine in follicular lymphoma.
US Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| NDA016785 (cancelled) | Matulane (Leadiant Biosciences, Inc.) | Capsule | Not listed in the data compiled for this report |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (alkylating-type agent) |
| Myelosuppression Risk | Please refer to the package insert warnings and precautions. The graph-based contraindication data flag thrombocytopenia, leukopenia and anemia. |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Complete blood count (with platelets), liver and renal function. Neurological status should also be monitored, given the peripheral neuropathy flag. |
| Handling Protection | Must follow cytotoxic drug handling regulations |
Safety Considerations
- Contraindications (knowledge-graph signals, not label text): liver failure and liver disease, kidney disease, gallbladder disease, thrombocytopenia, leukopenia, anemia (including macrocytic anemia), blood coagulation disease, peripheral neuropathy and peripheral nervous system disease, infectious disease (including fungal infection and dermatophytosis), pyoureter, and substance abuse/dependence.
- Drug Interactions: 100 interactions were found. Many are major, notably with sympathomimetics and serotonergic or anorectic agents: isometheptene, bupropion, morphine, lorcaserin, diethylpropion, phentermine, dexfenfluramine, fenfluramine, mazindol and ephedrine. Major interactions were also found with the 5-HT3 antagonists dolasetron, palonosetron, ondansetron and granisetron. Moderate interactions include epinephrine (several forms) and metoclopramide. Levofloxacin is a minor interaction.
- Other signals: Animal carcinogenicity studies (NCI bioassay) and survivor cohorts report secondary malignancy and gonadotoxicity risks with procarbazine-containing regimens.
Please also refer to the package insert for full safety information, as label warnings were not available in the data compiled for this report.
Conclusion and Next Steps
Decision: Hold
Rationale: The evidence is limited to a small case report, a cohort description of the PEP-C regimen and background literature. The two registered trials either terminated early (6 patients) or do not test procarbazine. The US license is cancelled, the mechanism of action is unavailable, and the safety profile (myelosuppression, carcinogenicity, interactions) calls for caution. Safety screening cannot proceed without the package insert.
To proceed, the following is needed:
- FDA package insert warnings and contraindications (a blocking gap for safety screening)
- Mechanism of action data (for example from DrugBank)
- Verification of whether the regimen in NCT00003113 contains procarbazine
- Prospective or retrospective data on procarbazine-containing regimens (such as PEP-C) in follicular lymphoma
- A review of the regulatory pathway, given that the only US license is cancelled
Other Predicted Indications (Not Recommended for Advancement)
| Predicted Indication | TxGNN Score | Evidence Level | Decision | Comment | |——|——|——|——|——| | Neuroblastoma | 99.21% | L4 | Hold | Only an in vitro study and toxicity literature. No trials, and the carcinogenicity and gonadotoxicity signals argue for caution in children. | | Ganglioneuroblastoma | 99.21% | L5 | Hold | Model score only, no trials or literature | | Retroperitoneal neoplasm | 99.14% | L5 | Hold | Broad anatomical category, no specific mechanism assignable | | Vertebral anomalies and variable endocrine and T-cell dysfunction | 99.07% | L5 | Hold | Rare congenital syndrome with no plausible link to a cytotoxic agent; likely a graph artifact |
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.