Copyright Blackwell Munksgaard 2004
Eur J Haematol 2004: 72: 441–443 Printed in UK. All rights reserved
EUROPEAN JOURNAL OF HAEMATOLOGY
Case report
Sustained cytogenetic response after discontinuation of imatinib mesylate in a patient with chronic myeloid leukaemia Ghanima W, Kahrs J, Dahl TG III, Tjonnfjord G. Sustained cytogenetic response after discontinuation of imatinib mesylate in a patient with chronic myeloid leukaemia. Eur J Haematol 2004: 72: 441–443. Blackwell Munksgaard 2004.
Abstract: A 58-yr-old woman was diagnosed with Ph+ chronic myeloid leukaemia in May 2001. She was initially treated with hydroxyurea and subsequently with interferon-a (IFN-a). Imatinib mesylate was started in April 2002 after failure of IFN-a to induce a cytogenetic response. The patient remained on treatment with imatinib mesylate for 3 months during which she suffered daily fever resulting in discontinuation of the treatment. Response evaluation performed shortly after discontinuing imatinib mesylate revealed a complete cytogenetic remission and a substantial molecular response. Fifteen months later, she was still enjoying a major cytogenetic response. This case illustrates that a short course of imatinib mesylate may result in a sustained haematological and cytogenetic response.
A 58-yr-old woman was diagnosed with Ph+ chronic myeloid leukaemia (CML) in May 2001 and her complete blood count at diagnosis is shown in Table 1. The blood smear showed a left shift of the granulocyte series with 1% myeloblasts. The bone marrow smear was hypercellular and dominated by granulocytopoiesis (83% of the nucleated cells) with 3% myeloblasts. Erythropoiesis accounted for 12% and lymphocytes for 2% of the nucleated cells. The cytogenetic analysis revealed 46, XX, t(9;22)(q34;q11) [15]. Hasford score at diagnosis was 725 (1). The patient was initially treated with hydroxyurea (HU), and a complete haematological response was achieved within short time. HU was continued for approximately 5 months. The patient had no HLA-matched sibling, and she was not considered a candidate for matchedunrelated allogeneic haematopoietic stem cell transplantation. Her treatment was therefore changed to interferon-a (IFN-a) in October 2001. The IFN dose was gradually escalated to 4 million U/m2/d and was continued for 6 months. She developed
Waleed Ghanima1, Johannes Kahrs1, Tobias Gedde Dahl III2, Geir E. Tjonnfjord2 1
Medical Department, Section of Haematology, Østfold Hospital, Fredrikstad, Fredrikstad, Norway; 2Medical Department, Section of Haematology, Rikshospitalet University Hospital, Oslo, Norway
Key words: chronic myeloid leukaemia; imatinib mesylate; cytogenetic response; BCR-ABL Correspondence: Waleed Ghanima, Medical Department, Section of Haematology, Østfold Hospital, Fredrikstad, 1603 Fredrikstad, Norway Tel: +47 41303440 Fax: +47 69860952 e-mail:
[email protected] Accepted for publication 23 February 2004
substantial side effects: lethargy, muscle and joint pain, anorexia, weight loss and near-syncope attacks. Response evaluation performed 6 months after starting IFN-a therapy revealed no cytogenetic response (Table 1). Due to lack of a cytogenetic response at that point, she was switched to imatinib mesylate 400 mg/d in April 2002. Soon after imatinib mesylate was initiated, she began complaining of daily fever, sweating and back pain. Investigations disclosed a persistently elevated ESR (68 mm/ h) with no concomitant elevation of CRP (13 mg/ mL). A chest X-ray and a high-resolution CT examination of the lung were both normal. Mycobacterium avium-intracellulare was grown in one of four sputum cultures, but the finding was not considered to be clinically significant. The patient discontinued imatinib mesylate on her own accord in July 2002, due to persistent fever. The fever and sweating disappeared within a day of stopping the drug, and her general condition improved significantly. She informed her physician about stopping imatinib mesylate at her scheduled follow-up visit in September 2002. Response evaluation performed at 441
Ghanima et al. Table 1. Laboratory data at diagnosis and during the follow-up May 2001
Oct. 2001
Apr. 2002
Oct. 2002
Feb. 2003
Oct. 2003
Nov. 2003
Jan. 2004
Hb (g/dL) WBC (·109/L) Neutrophils (·109/L) Lymphocytes (·109/L) Monocytes (·109/L) Basophils (·109/L) Eosinophils (·109/L) Platelet (·109/L) Treatment Karyotype
12 25 16.8 7.4 0.3 0.3 0.1 876 HU t(9;22)(q34;q11)[15]
12.4 4.5 2.2 1.9 0.2 0.03 0.01 258 IFN NP
10.2 4.8 2.8 1.5 0.42 0.00 0.01 176 Imatinib mesylate t(9;22)(q34;q11)[15]
13.7 5.3 2.8 2.1 0.2 0.00 0.06 225 No treatment 46 XX
NP NP
NP NP
NP NP
Negative Positive 0.036%2
13.6 8.1 3.6 4.2 0.3 0.04 0.05 280 No treatment t(9;22)(q34;q11)[1] 46, XX [24] NP NP NP
13.4 7.4 3.3 3.4 0.4 0.02 0.09 271 No treatment NP
BCR-ABL (RT-PCR) BCR-ABL (nested PCR) BCR-ABL (quant. PCR)1
12.8 4.9 2.1 2.3 0.3 0.00 0.09 273 No treatment t(9;22)(q34;q11)[3] 46, XX [12] Negative Positive Negative3
13.6 9.3 5.8 2.9 0.4 0.09 0.10 341 No treatment t(9;22)(q34;q11)[2] 46, XX [13] Positive NP 3.4%
Positive NP 1.1%
WBC, white blood cell count; HU, hydroxyurea; IFN-a, interferon a; NP, not performed. Quantitative PCR; results expressed as the ratio BCRABL/ABL; all PCR-assays were performed at the same laboratory. 2 The sample was re-analysed with quantitative real-time RT-PCR assay in Feb. 2004; RNA used for the assay was extracted from frozen leucocytes. 3 The sample was re-analysed with quantitative real-time RT-PCR assay in Feb. 2004; stored RNA material was used for the analysis. The negative results might be due to sampling or RNA degradation, as both RT-PCR assays, performed on that sample, were negative. 1
that point (Table 1) disclosed a complete cytogenetic remission, negative RT-PCR, weakly positive nested-PCR analysis (b3a2), and a positive quantitative real-time RT-PCR (BCR-ABL:BCR ¼ 0.036%). A scheduled visit in February 2003 revealed signs of cytogenetic relapse with the reappearance of the Ph+ chromosome in three of 15 metaphases (Table 1). The patient was re-examined in October and November 2003 and in January 2004. She looked healthy and had no clinical signs of disease. Table 1 shows the results of the laboratory work-up performed at these visits. Discussion
Imatinib mesylate is presently considered by most physicians to be first line treatment for CML. However, long-term experience with this drug is limited and a lot of questions still remain to be answered. In previously untreated patients with CML in first chronic phase, imatinib mesylate induced complete cytogenetic responses in up to 74%, and the effect was durable with continuous treatment (2). In patients with late-chronic phase CML and in whom previous therapy with IFN-a had failed, the rate of complete cytogenetic response was 40% (3). Our patient achieved a complete cytogenetic remission after 3 months of treatment with imatinib mesylate, following failure of IFN-a to induce any cytogenetic response. As the patient was not a candidate for haematopoietic stem cell transplantation, molecular analysis was only performed when the patient achieved a complete cytogenetic response. The first PCR analysis, performed 3 months after discontinuing imatinib mesylate, revealed a substantial molecular response. However, 442
we cannot disregard the possibility that IFN-a might have contributed to this outcome. The patient chose to discontinue treatment with imatinib mesylate because of persistent fever. About 13% of patients treated with this drug develop fever with 0.7% developing grade 3–4 pyrexia (3). The fever disappeared immediately after the discontinuation of imatinib mesylate in our patient, which is consistent with a causal relationship. To our knowledge, there are no previous reports on the duration of cytogenetic response after discontinuation of imatinib mesylate. Our patient is still enjoying a major cytogenetic response 18 months after stopping imatinib mesylate. As expected, the results of the PCR assays showed increasing number of BCR-ABL transcripts in the peripheral blood in line with the evidence of early cytogenetic relapse in the bone marrow. This case illustrates that a short course of imatinib mesylate may induce a long lasting haematological and cytogenetic response. As our patient had low risk CML at diagnosis, this might have contributed to this favourable outcome. It has recently been shown that the highest proportion of molecular responses was achieved in patients with low risk CML when treated with imatinib mesylate (4). This case may indicate that this drug may be administered intermittently leading to reducing the cost of treatment and the risk of developing resistance. References 1. Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic
Cytogenetic response in CML patient myelogenous leukemia treated with interferon alfa. J Natl Cancer Inst 1998;90:850–858. 2. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994–1004. 3. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in
chronic myelogenous leukaemia. N Engl J Med 2002;346:645–652. 4. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukaemia. N Engl J Med 2003;349:1423–1432.
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