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Bending the Curve Trial by Trial
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Nitrogen mustards and oxazaphosphorinesIn useDerivative of an earlier drugNeeds review

Chlorambucil

Also known as Leukeran, CB 1348

An oral aromatic nitrogen mustard reported in malignant lymphoma trials in 1955. Its 2011 US label lists chronic lymphatic leukaemia and malignant lymphomas; a 2015 review says it was the standard of care for chronic lymphocytic leukaemia for many decades.

From discovery to approval

  1. c. 1955 · Earliest report found

    Galton and colleagues' 1955 report of trials of p-(di-2-chloroethylamino)-phenylbutyric acid (CB 1348) in malignant lymphoma is the earliest paper found on the compound; its chemical name matches the Leukeran label's name for chlorambucil. A 1953 chemistry paper on carboxylic derivatives of N,N-di-2-chloroethylaniline does not name chlorambucil in its title, so no synthesis date is claimed.[2][3][1]

  2. 1957-03-18 · FDA regular · 2 years after first description

    Leukeran, NDA 010669, original approval, classed as a new molecular entity with priority review in the Drugs@FDA history. The original label is not available there, so the indication at approval is not stated here; the 2011 label lists chronic lymphatic leukaemia and malignant lymphomas including lymphosarcoma, giant follicular lymphoma and Hodgkin disease. The type regular is an inference: no accelerated-approval wording was found.[4]

How it works

The 2011 US label calls it an aromatic nitrogen mustard derivative and alkylating agent that interferes with DNA replication and induces apoptosis through accumulation of cytosolic p53 and activation of Bax, a promoter of apoptosis.[1]

Where it came from and why

No source states why chlorambucil was made. The 2011 label describes it as an aromatic nitrogen mustard derivative.

Cancers

  • Chronic lymphocytic leukaemia

    The 2011 US label lists chronic lymphatic (lymphocytic) leukaemia and says the drug is not curative in the listed disorders but may produce clinically useful palliation.[1]

  • Malignant lymphomas

    The 2011 label lists malignant lymphomas including lymphosarcoma, giant follicular lymphoma and Hodgkin disease; a 1955 paper reports clinical trials of CB 1348 in malignant lymphoma (from its title).[2]

  • Chronic lymphocytic leukaemia (early steroid combination)

    A 1961 paper is titled as a report on the use of chlorambucil and steroids in chronic lymphocytic leukaemia.[5]

  • Chronic lymphocytic leukaemia with coexisting conditions

    In a randomised trial of 781 previously untreated patients, adding obinutuzumab or rituximab to chlorambucil prolonged progression-free survival compared with chlorambucil alone, as reported by the authors.[6]

Worth knowing

  • A 2015 review says that for many decades chlorambucil was the standard of care for chronic lymphocytic leukaemia, until purine-analogue-based chemoimmunotherapy replaced it, and that it retains a role as a backbone for antibody combinations in older patients unfit for standard treatment.[7]
  • In a three-arm trial that randomised 509 previously untreated patients between 1990 and 1994, fludarabine produced higher response rates and longer progression-free survival than chlorambucil, with no significant difference in overall survival; the arm combining the two drugs was closed early for toxicity.[8]
  • In the CLL11 trial abstract, median progression-free survival was 26.7 months with obinutuzumab plus chlorambucil and 11.1 months with chlorambucil alone (hazard ratio 0.18, 95% CI 0.13 to 0.24).[6]

On this site

References

  1. U.S. Food and Drug Administration. Leukeran (chlorambucil) tablets, prescribing information, NDA 010669/S-032 (action date 28 October 2011). Source
  2. GALTON DA, ISRAELS LG, NABARRO JD, TILL M. Clinical trials of p-(di-2-chloroethylamino)-phenylbutyric acid (CB 1348) in malignant lymphoma. Br Med J. 1955;2(4949):1172-6. PubMedDOI
  3. Everett JL, Roberts JJ, Ross WCJ. 486. Aryl-2-halogenoalkylamines. Part XII. Some carboxylic derivatives of NN-di-2-chloroethylaniline. Journal of the Chemical Society (Resumed). 1953;:2386. DOI
  4. U.S. Food and Drug Administration. Drugs@FDA: Approval date(s) and history, NDA 010669 (Leukeran, chlorambucil). Accessed 20 October 2026. Source
  5. GALTON DA, WILTSHAW E, SZUR L, DACIE JV. The use of chlorambucil and steroids in the treatment of chronic lymphocytic leukaemia. Br J Haematol. 1961;7:73-98. PubMedDOI
  6. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-10. PubMedDOI
  7. Goede V, Eichhorst B, Fischer K, Wendtner CM, Hallek M. Past, present and future role of chlorambucil in the treatment of chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56(6):1585-92. PubMedDOI
  8. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343(24):1750-7. PubMedDOI