Clofarabine
| Evidence Level: L2 | Predicted Indications: 10 |
Table of Contents
- Clofarabine
- Clofarabine: From Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia to Myeloid Leukemia
Clofarabine: From Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia to Myeloid Leukemia
One-Sentence Summary
Clofarabine is a purine nucleoside analog chemotherapy. Per the trial registry descriptions, it is FDA-approved for pediatric patients (1 to 21 years) with relapsed or refractory acute lymphoblastic leukemia (ALL). The TxGNN model predicts it may be effective for myeloid leukemia, with 50 clinical trials and 20 publications currently supporting this direction. Most of these are Phase 1/2 studies, and no Phase 3 trial appears in the supplied data for this indication.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Pediatric relapsed/refractory ALL (from trial registry descriptions; the license records supplied contain no indication text) |
| Predicted New Indication | Myeloid leukemia |
| TxGNN Prediction Score | 99.88% |
| Evidence Level | L2 |
| US Market Status | ✓ Marketed |
| Number of NDAs | 8 (the 5 listed are generic ANDA injections) |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the source record. The published literature in the evidence set describes clofarabine as a second-generation purine nucleoside analog. It inhibits ribonucleotide reductase and DNA polymerase, which depletes the deoxynucleotide pools needed for DNA replication. It also disrupts mitochondrial membranes and triggers apoptosis. These effects should work well in rapidly dividing leukemic blasts.
ALL and myeloid leukemia are both acute leukemias treated with nucleoside-analog-based chemotherapy. Clofarabine was designed to combine the best features of fludarabine and cladribine, and it resists enzymatic degradation. Combination regimens with cytarabine, its DNA-damaging partner, have been tested repeatedly in acute myeloid leukemia (AML). A patient-level meta-analysis in ALL supports its established indication.
Two limits apply. First, the mechanism rests on general drug-class knowledge rather than the source MOA field. Second, many of the supporting trials use clofarabine as one part of a transplant conditioning or combination regimen. Its independent contribution is therefore hard to separate.
Clinical Trial Evidence
The table lists 10 of the 50 trials found for this prediction.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00373529 | Phase 2 | Completed | 116 | Single-agent clofarabine in older adults with untreated AML unsuitable for intensive chemotherapy |
| NCT00065143 | Phase 2 | Completed | 60 | Clofarabine plus cytarabine in patients ≥50 years with untreated AML or high-risk MDS |
| NCT00775593 | Phase 2 | Completed | 60 | Clofarabine plus temsirolimus in older patients with relapsed/refractory AML |
| NCT00088218 | Phase 2 | Completed | 95 | Randomized: clofarabine alone vs. with low-dose cytarabine in untreated AML/high-risk MDS, age ≥60 |
| NCT00932412 | Phase 2 | Completed | 735 | Randomized: clofarabine/intermediate-dose cytarabine (CLARA) vs. high-dose cytarabine as consolidation in younger AML patients |
| NCT01295307 | Phase 2 | Completed | 86 | Clofarabine salvage therapy in relapsed/refractory AML |
| NCT01025154 | Phase 2 | Completed | 63 | Clofarabine, idarubicin and cytarabine as induction in AML patients aged 18-60 |
| NCT00838240 | Phase 1/2 | Unknown | 114 | Clofarabine added to cytarabine and idarubicin induction (EORTC/GIMEMA AML-14A); results unconfirmed |
| NCT00469014 | Phase 2 | Completed | 72 | Busulfan-fludarabine-clofarabine conditioning before allogeneic transplant; clofarabine’s independent effect is unclear |
| NCT05917405 | Phase 2 | Recruiting | 302 | Clofarabine/busulfan vs. fludarabine/busulfan reduced-intensity conditioning in adult AML (registered as Phase 2; title says Phase III) |
Several other trials in the set were terminated or withdrawn with 0-6 patients and are uninformative (for example NCT01960387, NCT04002115 and NCT00939653).
Literature Evidence
The table lists 10 of the 20 publications found for this prediction.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 31246522 | 2019 | Randomized Phase III (AML08, pediatric) | J Clin Oncol | Clofarabine can replace anthracyclines and etoposide in remission induction for childhood AML |
| 18565853 | 2008 | Randomized study | Blood | Clofarabine vs. clofarabine plus low-dose cytarabine as front-line therapy in patients ≥60 with AML or high-risk MDS |
| 32187883 | 2020 | Phase 2 cohort | Cancer Med | Clofarabine, cytarabine and mitoxantrone in refractory/relapsed AML: high response rates and an effective bridge to transplant |
| 31905904 | 2019 | Cohort analysis | Cancers | Clofarabine-based consolidation (CLARA) improved relapse-free survival in younger adults with micro-complex karyotype AML |
| 36336258 | 2023 | Cohort | Transplant Cell Ther | Clofarabine plus busulfan myeloablative conditioning in active myeloid malignancies |
| 31637757 | 2020 | Phase I/II trial | Am J Hematol | Clofarabine with low-dose TBI as non-myeloablative conditioning for AML patients unfit for intense regimens |
| 29773602 | 2018 | Phase IB | Haematologica | Recommended phase II dose of clofarabine with high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory AML |
| 22957815 | 2013 | Review | Leuk Lymphoma | The role of clofarabine in AML; describes its mechanism as a purine nucleoside analog |
| 25457773 | 2015 | Review | Crit Rev Oncol Hematol | Clofarabine in adult AML, covering monotherapy and combination strategies |
| 17852710 | 2007 | Review | Leuk Lymphoma | Clofarabine “past, present, and future”; three proposed mechanisms of action |
US Market Information
Clofarabine is marketed in the US as injection. The 5 main authorizations below are all generic ANDAs, and the records supplied contain no approved-indication text.
| Authorization Number | Product Name | Dosage Form | Manufacturer |
|---|---|---|---|
| ANDA212457 | Clofarabine | Injection | Eugia US LLC |
| ANDA213461 | Clofarabine | Injection | Meitheal Pharmaceuticals Inc. |
| ANDA205375 | Clofarabine | Injection | Dr. Reddy’s Laboratories Inc |
| ANDA207831 | Clofarabine | Injection | Gland Pharma Limited |
| ANDA204029 | Clofarabine | Injection | Fresenius Kabi USA, LLC |
Cytotoxicity
The evidence pack contains no DrugBank toxicity data. The entries below are class-based and should be confirmed against the package insert.
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (purine nucleoside analog antimetabolite) |
| Myelosuppression Risk | High (expected with acute leukemia dosing; grade >3 hematologic and infectious toxicity was reported in a Spanish adult ALL series, PMID 22431002) |
| Emetogenicity Classification | Low to moderate (class-based estimate) |
| Monitoring Items | CBC with differential, liver and renal function, electrolytes |
| Handling Protection | Must follow cytotoxic drug handling regulations |
Safety Considerations
Please refer to the package insert for safety information. No drug-drug interaction records were found in the evidence pack.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Many completed Phase 2 trials, including single-agent studies in older adults and randomized studies, support clofarabine activity in AML. The mechanism is biologically plausible, and the drug is already marketed. However, no Phase 3 result for myeloid leukemia is in the supplied data, and several trials use clofarabine only as part of a combination or conditioning regimen. That is why the evidence level is L2 rather than L1.
The other ALL predictions (ranks 2 and 8) are likely on-label uses. The remaining low-evidence predictions (ganglioneuroblastoma, vertebral anomalies syndrome, retroperitoneal neoplasm, CLL/SLL subtypes) should stay on Hold.
To proceed, the following is needed:
- FDA package insert warnings and contraindications (a blocking data gap for safety screening)
- Structured mechanism of action data from DrugBank
- Review of the completed Phase 3 trial NCT00317642 (clofarabine plus cytarabine vs. cytarabine alone, relapsed/refractory AML, n=326). It appears in the ALL trial list and could raise the evidence level if its results are positive.
- Separate confirmation of the original indication from the FDA label, since the supplied license records contain no indication text
- A safety monitoring plan covering myelosuppression, infection risk and organ toxicity
This report is for research reference only and does not constitute medical advice. Repurposing candidates require clinical validation before application.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.