Correspondence
Campath-1H–Induced Complete Remission of Chronic Lymphocytic Leukemia despite p53 Gene Mutation and Resistance to Chemotherapy
N Engl J Med 2002; 347:452-453August 8, 2002
- Article
To the Editor:
Treatment of chronic lymphocytic leukemia (CLL) with fludarabine results in a higher remission rate and longer progression-free survival than do alkylating agents.1 Patients who have no response to fludarabine have a dismal prognosis, with a median survival of 10 months.2 In these patients the anti–CD52 antibody alemtuzumab (Campath-1H, MabCampath) has recently shown promising results, with an overall response rate of 33 percent.3 The molecular mechanisms of its action and the biologic factors associated with the clinical response are not well defined.
A 72-year-old woman was given a diagnosis of CLL, Binet stage A, in August 1997. Because of rapidly rising lymphocyte counts, she received treatment with chlorambucil, but the disease progressed to stage B and was subsequently refractory to treatment with four cycles of mitoxantrone, vincristine, and prednisone (November 1999 to February 2000) and three cycles of fludarabine (March to June 2000). In August 2000, the patient was admitted to our hospital. She had stage C disease with a lymphocyte count of over 100,000 per cubic millimeter and severe myelosuppression requiring weekly transfusions of erythrocytes and platelets. There was almost 100 percent infiltration of the bone marrow by CLL but no marked lymphadenopathy, and the spleen was palpable at the costal margin. Treatment with 30 mg of Campath-1H was given intravenously three times per week for 12 weeks. (L&I Partners, San Antonio, Tex., through ILEX Services, Edinburgh, United Kingdom, provided Campath-1H within the CAM511 compassionate-use program.) Within seven days, the lymphocyte counts dropped from 110,000 to 800 per cubic millimeter, and complete remission according to the criteria of the National Cancer Institute was achieved in October 2000 (Figure 1Figure 1
Response to Campath-1H in a Patient with CLL, a Chromosome 17p Deletion, a Point Mutation in p53, and No Response to Chlorambucil, Mitoxantrone, Vincristine, Prednisone, and Fludarabine.). At the time of follow-up evaluation in February 2002, the bone marrow was free of CLL infiltration on cytologic, histologic, and flow-cytometric examinations. The patient resumed her normal daily activities, gained 9 kg (20 lb) in weight, and is currently in her 18th month of sustained complete remission. Genetic analysis of the CLL cells obtained before Campath-1H therapy revealed unmutated V H genes and a chromosome 17p deletion, with a point mutation of the remaining p53 allele.Biologic risk factors such as a mutation in V H genes and genomic aberrations have recently been identified as independent prognostic factors in CLL. Among these, the 17p deletion identifies the subgroup of patients with the worst prognosis, with a median survival of 32 months.4 Moreover, the 17p deletion and p53 gene mutation were shown to predict treatment failure with fludarabine.5 The complete remission achieved with Campath-1H in our patient with CLL despite the inactivation of p53 suggests that the mechanism of action is independent of p53 and indicates a novel treatment option for this group of patients.
5 ReferencesStephan Stilgenbauer, M.D.
Hartmut Döhner, M.D.
University of Ulm, D-89081 Ulm, Germany
stephan.stilgenbauer@medizin. uni-ulm. de 1
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Keating MJ ,Flinn I ,Jain V , et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 2002;99:3554-3561
CrossRef | Web of Science | Medline4
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Full Text | Web of Science | Medline5
Dohner H ,Fischer K ,Bentz M , et al. p53 Gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995;85:1580-1589
Web of Science | Medline
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