Clofarabine

Evidence Level: L1

Predicted Indications: 8

Clofarabine

Pharmacist Assessment Report

Clofarabine: Purine nucleoside analog (inhibitor of ribonucleotide reductase and DNA polymerase) → myeloid leukemia

One-Sentence Summary

Clofarabine is a purine nucleoside analog anticancer drug. The TxGNN model predicts it may be effective for myeloid leukemia, with 44 clinical trials and 20 publications compiled for this direction, including a completed Phase 3 randomized trial.

Quick Overview

Item	Content
Original Indication	Not recorded in the local data
Predicted New Indication	myeloid leukemia
TxGNN Prediction Score	0.9988
Evidence Level	L1
India Market Status	Listed in a compiled Indian medicine price dataset (2 of 2) – CDSCO approval status is not included in this data
Number of Listed Products	2 (valid: 2)
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Clofarabine is a second-generation purine nucleoside analog. It inhibits ribonucleotide reductase and DNA polymerase, which depletes the nucleotide pool needed for DNA replication, and it induces apoptosis through mitochondrial pathways. Detailed mechanism-of-action data are not available in the data compiled for this report, so this description rests on established pharmacology described in the cited reviews.

These mechanisms act on rapidly dividing leukemic cells, whether of lymphoid or myeloid origin. This makes it plausible that activity seen in lymphoblastic leukemia extends to myeloid leukemia. Reviews on clofarabine in acute myeloid leukemia (AML) describe single-agent activity and good tolerability in combinations, particularly in older adults and in relapsed or refractory disease.

Direct clinical evidence is substantial. It includes a completed Phase 3 randomized trial in older adults with newly diagnosed AML (n=727) and a completed double-blind Phase 3 trial of clofarabine plus cytarabine versus cytarabine alone in relapsed or refractory AML (n=326), along with many Phase 1 and 2 studies.

Clinical Trial Evidence

The table lists the 10 most relevant of the 44 trials compiled.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT02085408	Phase 3	Completed	727	Clofarabine induction and post-remission therapy vs. standard daunorubicin/cytarabine, followed by decitabine maintenance or observation, in older adults with newly diagnosed AML
NCT00317642	Phase 3	Completed	326	Double-blind comparison of clofarabine plus cytarabine vs. cytarabine alone in relapsed or refractory AML, age 55 and older
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 or refractory AML
NCT00044889	Phase 2	Completed	40	Single-arm study of clofarabine in adults with refractory or relapsed AML
NCT00067028	Phase 2	Completed	116	Clofarabine with cytarabine and/or idarubicin in first relapse or primary refractory AML, high-grade MDS, or myeloid blast-phase CML
NCT01193400	Phase 2	Terminated	75	Clofarabine plus low-dose cytarabine induction and consolidation in AML patients aged 60 or older
NCT01101880	Phase 2	Completed	50	Clofarabine with high-dose cytarabine and G-CSF priming in newly diagnosed AML, advanced MDS or myeloproliferative neoplasm
NCT01643668	Phase 2	Completed	34	Busulfan/clofarabine reduced-intensity conditioning before allogeneic transplant
NCT00838240	Phase 1/2	Unknown	114	Clofarabine added to cytarabine and idarubicin induction in untreated intermediate/high-risk AML or high-risk MDS

Literature Evidence

The table lists the 10 most relevant of the 20 publications compiled. Most are reviews; no randomized trial publication is included.

PMID	Year	Type	Journal	Key Findings
22957815	2013	Review	Leukemia & Lymphoma	Role of clofarabine in AML; inhibits ribonucleotide reductase and DNA polymerase, with improved stability over fludarabine and cladribine
25457773	2015	Review	Critical Reviews in Oncology/Hematology	Clofarabine in adult AML, from monotherapy to combination strategies in first- and second-line protocols
22170975	2012	Review	Annals of Pharmacotherapy	Efficacy and tolerability of clofarabine in newly diagnosed AML in older adults
19852733	2009	Review	Future Oncology	Single-agent activity compares favorably with standard antileukemia agents; safe in combinations
16316309	2005	Review	Expert Opinion on Pharmacotherapy	Clofarabine in AML and ALL; single-agent activity in acute leukemias
19463072	2009	Review	Expert Opinion on Pharmacotherapy	Activity in AML, ALL and MDS as a single agent and in combinations
21591997	2011	Review	Expert Opinion on Investigational Drugs	Clofarabine in myelodysplastic syndromes, including possible effect on DNA methylation at low doses
36336258	2023	Clinical study	Transplantation and Cellular Therapy	Clofarabine plus busulfan myeloablative conditioning before transplant in active myeloid malignancies
18780321	2008	Review	Cancer	Searching for clofarabine combinations in high-risk AML
24081220	2014	Case report	J Oncol Pharm Pract	Kidney toxicity in a patient with refractory AML treated with clofarabine

India Market Information

Authorization Number	Product Name	Dosage Form	Approved Indication
87595	Farabine 20mg Injection	vial of 1 Injection	Not recorded
43978	Cfara Injection	vial of 20 ml Injection	Not recorded

Cytotoxicity

Item	Content
Cytotoxicity Classification	Conventional cytotoxic (purine nucleoside analog)
Myelosuppression Risk	High (neutropenia, anemia and thrombocytopenia are listed among related concerns)
Emetogenicity Classification	Please refer to the package insert warnings and precautions
Monitoring Items	Complete blood count with differential, liver and renal function (kidney toxicity has been reported), blood pressure
Handling Protection	Follow cytotoxic drug handling regulations

Safety Considerations

Conditions of concern: Clofarabine is flagged as a concern in patients with liver disease, gallbladder disease, kidney failure, thrombocytopenia, neutropenia, agranulocytosis, anemia, hyperbilirubinemia (including Gilbert syndrome), hypotensive disorder, capillary leak syndrome, and active infections (including fungal infections). These are not taken from label text and should be confirmed against the package insert.
Drug Interactions: 466 interactions were identified. The 20 listed are all moderate, including acarbose, pioglitazone, amphotericin B (including lipid, cholesteryl sulfate and liposomal forms), bupropion, mesalazine, balsalazide, clarithromycin, clotrimazole, kanamycin, levofloxacin, minocycline, naltrexone, neomycin, nicotinamide, nitisinone and olsalazine.
Published case: Kidney toxicity has been reported in an adult with refractory AML (PMID 24081220).

Package insert warnings and contraindications for the Indian products were not available; please refer to the package insert.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Two completed Phase 3 randomized trials and many Phase 2 studies directly address clofarabine in AML. The drug is marketed in India. However, results from these trials are not summarized in the data compiled, and the safety profile of this cytotoxic agent requires careful management.

To proceed, the following is needed:

Outcome results (response, survival) from the two Phase 3 trials
Package insert warnings and contraindications for the Indian products
Detailed mechanism of action data
A monitoring plan for myelosuppression, kidney and liver function, and infection risk, particularly in older adults
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.