Clofarabine
| Evidence Level: L1 | Predicted Indications: 10 |
Table of Contents
Clofarabine: From Acute Lymphoblastic Leukemia to Myeloid Leukemia
One-Sentence Summary
Clofarabine is a purine nucleoside analogue chemotherapy, originally used to treat acute lymphoblastic leukemia (ALL). The TxGNN model predicts it may be effective for myeloid leukemia, with 45 clinical trials (including 2 completed Phase 3 trials) and 19 publications currently supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acute lymphoblastic leukemia (the Singapore licence record contains no indication text; this is taken from the drug's known indications) |
| Predicted New Indication | Myeloid leukemia |
| TxGNN Prediction Score | 99.88% |
| Evidence Level | L1 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known pharmacology, clofarabine is a second-generation purine nucleoside analogue. It inhibits ribonucleotide reductase and DNA polymerase, depleting the building blocks for DNA synthesis, and it induces apoptosis. These actions target rapidly dividing cells.
Lymphoid and myeloid leukemic blasts are both rapidly proliferating and both depend on DNA synthesis. This is why a drug proven in ALL may also work in acute myeloid leukemia (AML). Published reviews describe single-agent activity in AML that compares favorably with standard agents. Clofarabine has also been combined with cytarabine and other drugs in many AML trials and used in transplant conditioning. This mechanistic link rests on class pharmacology rather than recorded MOA data.
Clinical Trial Evidence
The table lists the 10 most relevant trials, prioritising randomised and completed studies.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02085408 | Phase 3 | Completed | 727 | Clofarabine induction/post-remission vs daunorubicin + cytarabine, then decitabine or observation, in older adults (≥60) with newly diagnosed AML |
| NCT00317642 | Phase 3 | Completed | 326 | Double-blind comparison of clofarabine + cytarabine vs cytarabine alone in relapsed/refractory AML, age ≥55 |
| NCT00454480 | Phase 2/3 | Completed | 2000 | Treatment development programme for older patients with AML and high-risk MDS |
| NCT01295307 | Phase 2 | Completed | 86 | Clofarabine salvage therapy in relapsed/refractory AML |
| NCT00067028 | Phase 2 | Completed | 116 | Randomised comparison of clofarabine with cytarabine and/or idarubicin in relapsed AML, high-grade MDS and myeloid blast-phase CML |
| NCT00044889 | Phase 2 | Completed | 40 | Single-arm study of clofarabine in adults with refractory/relapsed AML |
| NCT01101880 | Phase 2 | Completed | 50 | Clofarabine + high-dose cytarabine + G-CSF priming in newly diagnosed AML or advanced MDS |
| NCT01193400 | Phase 2 | Terminated | 75 | Clofarabine + low-dose cytarabine induction and consolidation in AML patients ≥60; early termination limits conclusions |
| NCT01643668 | Phase 2 | Completed | 34 | Reduced-intensity busulfan/clofarabine conditioning before allogeneic transplant; single-arm |
| NCT00469014 | Phase 2 | Completed | 72 | Randomised busulfan-fludarabine-clofarabine conditioning for advanced AML, MDS and CML |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 22957815 | 2013 | Review | Leukemia & Lymphoma | Role of clofarabine in AML; inhibits ribonucleotide reductase and DNA polymerase, with better stability than its predecessors |
| 25457773 | 2015 | Review | Critical Reviews in Oncology/Hematology | Clofarabine in adult AML, from monotherapy to combination strategies |
| 19852733 | 2009 | Review | Future Oncology | Single-agent activity in AML compares favorably with current standard agents |
| 22170975 | 2012 | Review | Annals of Pharmacotherapy | Efficacy and tolerability in older adults with newly diagnosed AML |
| 16316309 | 2005 | Review | Expert Opinion on Pharmacotherapy | Single-agent activity in acute leukemias (AML and ALL) |
| 17852710 | 2007 | Review | Leukemia & Lymphoma | Three proposed mechanisms; expected synergy with other chemotherapy |
| 36336258 | 2023 | Clinical study | Transplantation and Cellular Therapy | Clofarabine + busulfan myeloablative conditioning for active myeloid malignancies |
| 21591997 | 2011 | Review | Expert Opinion on Investigational Drugs | Clofarabine in myelodysplastic syndromes; may affect DNA methylation at low doses |
| 24081220 | 2014 | Case report | J Oncol Pharm Pract | Kidney toxicity in an adult with refractory AML |
| 27621503 | 2015 | Review | Hospital Pharmacy | Clofarabine and cytarabine regimen for AML, covering preparation and administration |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN14026P | Evoltra Concentrate Solution for Infusion 1mg/ml | Solution, concentrate | Indication text not recorded in the data compiled for this report |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (purine nucleoside antimetabolite) |
| Myelosuppression Risk | High. The knowledge graph lists neutropenia, agranulocytosis, thrombocytopenia and anaemia as contraindication-related conditions, and trials report haematological and infectious toxicity |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | CBC with differential, liver function (bilirubin), renal function, blood pressure; kidney toxicity has been reported in the literature |
| Handling Protection | Must follow cytotoxic drug handling regulations |
Safety Considerations
- Conditions flagged in the knowledge graph (not label text): liver disease, gallbladder disease, hyperbilirubinemia (including Gilbert syndrome), kidney failure, uremia, thrombocytopenia, neutropenia, agranulocytosis, anaemia, hypotensive disorder, capillary leak syndrome, and infectious disease (including fungal infection and dermatophytosis).
- Drug Interactions: 100 interactions were found in the interaction databases. The 20 listed were all of moderate severity, including amphotericin B (several formulations), clarithromycin, levofloxacin, minocycline, kanamycin, neomycin, mesalazine, balsalazide, olsalazine, acarbose, pioglitazone, bupropion, naltrexone and nitisinone.
- Label warnings and contraindications: not available. Please refer to the package insert.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Two completed Phase 3 randomised trials (NCT02085408, n=727; NCT00317642, n=326) plus many Phase 2 studies support clofarabine in AML, which meets the L1 level. However, the data gathered here do not show whether these trials met their primary endpoints, and no summary results were retrieved. The drug is highly myelosuppressive and has organ-toxicity signals, so use needs strict safeguards.
To proceed, the following is needed:
- Review the published results of NCT02085408 and NCT00317642 (efficacy and survival outcomes)
- Obtain and review the HSA package insert, including approved indication, warnings and contraindications
- Confirm the mechanism of action from DrugBank
- Define a toxicity monitoring plan (blood counts, liver and kidney function) and an interaction check for concomitant drugs
- Clarify the Singapore-approved indication versus the proposed use
Other Predicted Indications (Brief)
- Precursor lymphoblastic lymphoma/leukemia and acute lymphoblastic leukemia: this is the approved use, not a new repurposing. Evidence level L2 with Phase 2 data and a patient-level meta-analysis (Proceed with Guardrails).
- Blast phase CML: L2, phase 1/2 evidence and a case series on bridging to transplant. This remains a research question.
- Neuroblastoma: L4, indirect evidence only (Hold).
- Ganglioneuroblastoma, vertebral anomalies with endocrine and T-cell dysfunction, retroperitoneal neoplasm, and two CLL/SLL subtypes: L5, no trials or literature (Hold).
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.