Clofarabine

From discovery to approval

1. c. 1980 · Earliest report found

   A 2005 review says clofarabine was synthesised early in the 1980s to combine the favourable properties of fludarabine and cladribine, and that development stalled until 1993. A 1992 paper on 2'-fluoro-2-halo arabinosyladenine derivatives is the earliest chemistry report found; its abstract does not name clofarabine.^[2][3][4]

2. 1993 · First use in people · 13 years after first description

   Two reviews state that the first phase I study, in patients with haematologic and solid malignancies, was started in 1993; one adds that animal toxicology studies at M. D. Anderson preceded it.^[2]

3. 2004-12-28 · FDA accelerated · 24 years after first description

   Treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. The letter says the use is based on the induction of complete responses and that randomized trials demonstrating increased survival or other clinical benefit have not been conducted; approved under the accelerated approval regulations (21 CFR 314.510).^[5]

4. 2006-05-29 · EMA exceptional · 26 years after first description

   Evoltra, marketing authorisation issued 29 May 2006 according to the EPAR page, which states it was authorised under exceptional circumstances. The page lists treatment of acute lymphoblastic leukaemia in paediatric patients who have relapsed or are refractory after at least two prior regimens and where no other treatment option is anticipated to result in a durable response (the page shows the current text).^[6]

5. 2022-07-18 · FDA converted · 42 years after first description

   Prior approval supplement (NDA 021673/S-027) with updates to the Indications and Clinical Trials sections. Under the heading 'Subpart H fulfilled' the letter states the NDA was approved under 21 CFR 314 Subpart H and that approval of this supplement fulfills the commitments under 21 CFR 314.510. The letter does not itself use the word 'converted'. FDA's list 'Verified Clinical Benefit | Cancer Accelerated Approvals' (opened 26 October 2026) records Clolar for relapsed or refractory pediatric ALL with an accelerated approval date of 12/28/2004 and a traditional approval date of 7/18/2022, which supports the type 'converted'.^[7]

How it works

Converted inside cells to the active triphosphate, which inhibits ribonucleotide reductase and DNA polymerases and is incorporated into DNA, lowering deoxynucleotide pools and inhibiting DNA synthesis and repair. The label also describes disruption of mitochondrial membranes.^[1]

Where it came from and why

Reviews say it was designed to overcome limitations of fludarabine and cladribine; a 2010 review lists greater resistance to deamination and phosphorolysis and higher affinity for deoxycytidine kinase.

Cancers

• Relapsed or refractory acute lymphoblastic leukaemia in children

  In a phase II study of 61 paediatric patients, the response rate was 30% (7 complete remissions, 5 complete remissions without platelet recovery and 6 partial remissions).^[8]

• Refractory and relapsed leukaemia in children (phase I)

  In a phase I study of 25 children the maximum tolerated dose was 52 mg/m2 per day for 5 days; 5 achieved complete remission and 3 partial remission.^[9]

Family and partners

Derived from: Fludarabine, Cladribine

Worth knowing

• A 2005 review calls clofarabine the first new drug for paediatric leukaemia approved in more than a decade, and the only one to receive approval for paediatric use before adult use.^[10]
• The FDA's 2004 letter states that the use is based on induction of complete responses and that randomised trials demonstrating increased survival or other clinical benefit had not been conducted.^[5]
• The EMA page says Evoltra was authorised under exceptional circumstances because the disease is rare and complete information could not be obtained.^[6]
• In the phase II study, median complete remission duration in patients who did not go on to transplantation was 6 weeks, and remissions were durable enough for some patients to proceed to haematopoietic stem-cell transplantation.^[8]

References

1. Novadoz Pharmaceuticals LLC. Clofarabine injection: prescribing information. DailyMed, set ID 26b2de66-6518-49ab-820e-492454cbc873, published 2 September 2026. Read 26 October 2026. Source
2. Faderl S, Gandhi V, Keating MJ, Jeha S, Plunkett W, Kantarjian HM. The role of clofarabine in hematologic and solid malignancies--development of a next-generation nucleoside analog. Cancer. 2005;103(10):1985-95. PubMedDOI
3. Ghanem H, Jabbour E, Faderl S, Ghandhi V, Plunkett W, Kantarjian H. Clofarabine in leukemia. Expert Rev Hematol. 2010;3(1):15-22. PubMedDOI
4. Montgomery JA, Shortnacy-Fowler AT, Clayton SD, Riordan JM, Secrist JA 3rd. Synthesis and biologic activity of 2'-fluoro-2-halo derivatives of 9-beta-D-arabinofuranosyladenine. J Med Chem. 1992;35(2):397-401. PubMedDOI
5. US Food and Drug Administration. Approval letter, NDA 21-673, Clolar (clofarabine) intravenous infusion, Genzyme Corporation; accelerated approval, 28 December 2004. Source
6. European Medicines Agency. Evoltra (clofarabine): European public assessment report page (authorised under exceptional circumstances; marketing authorisation issued 29/05/2006). Read 26 October 2026. Source
7. US Food and Drug Administration. Supplement approval letter (fulfillment of postmarketing requirement), Clolar (clofarabine) injection, NDA 021673/S-027, Genzyme Corporation; electronic signature date 18 July 2022. Source
8. Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006;24(12):1917-23. PubMedDOI
9. Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004;103(3):784-9. PubMedDOI
10. Pui CH, Jeha S. Clofarabine. Nat Rev Drug Discov. 2005;Suppl:S12-3. PubMedDOI