Correspondence

Tyrosine Kinase Inhibitors for Chronic Myelogenous Leukemia

N Engl J Med 2007; 357:1556-1558October 11, 2007

Article

To the Editor:

Schiffer (July 19 issue)1 discusses some of the adverse events associated with the use of BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia (CML). We would add hypothyroidism to the list of events presented in Table 1 of the article. Hypothyroidism has been reported in patients treated with imatinib for metastatic medullary thyroid carcinoma or gastrointestinal stromal tumors (GIST).2 An increase in levothyroxine replacement was necessary in some patients who had previously undergone a thyroidectomy. Similar effects have been reported with sunitinib malate, an oral tyrosine kinase inhibitor recently developed for the treatment of GIST and renal-cell carcinomas.3-5 The mechanism of the thyroid dysfunction is uncertain. Possible explanations include inhibition of the RET proto-oncogene, destructive thyroiditis through follicular-cell apoptosis, inhibition of peroxidase activity, and impaired iodine uptake. In our opinion, physicians prescribing tyrosine kinase inhibitors should test thyroid function before starting therapy and regularly monitor the thyrotropin level during treatment.

Gilles Defuentes, M.D.
Jean-Sébastien Bladé, M.D.
Olivier Berets, M.D.
Hôpital d'Instruction des Armées Percy, 92140 Clamart, France
gildef@club-internet.fr

5 References

1. 1

   Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med 2007;357:258-265
   Full Text | Web of Science | Medline

2. 2

   de Groot JW, Zonnenberg BA, Plukker JT, van Der Graaf WT, Links TP. Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther 2005;78:433-438
   CrossRef | Web of Science | Medline

3. 3

   Desai J, Yassa L, Marqusee E, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006;145:660-664
   Web of Science | Medline

4. 4

   Wong E, Rosen LS, Mulay M, et al. Sunitinib induces hypothyroidism in advanced cancer patients and may inhibit thyroid peroxidase activity. Thyroid 2007;17:351-355
   CrossRef | Web of Science | Medline

5. 5

   Mannavola D, Coco P, Vannucchi G, et al. A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake. J Clin Endocrinol Metab 2007;92:3531-3534
   CrossRef | Web of Science | Medline

To the Editor:

Dr. Schiffer states that “RT-PCR [reverse-transcriptase–polymerase-chain-reaction] analysis can be performed on peripheral blood, obviating the need for repetitive bone marrow examination.” We consider this contention to be misleading. Achieving a complete cytogenetic remission with imatinib results in improved event- and transformation-free survival.1 However, it is unclear whether achieving these responses earlier confers an advantage. Patients not in complete cytogenetic remission continuously face the risk of disease progression. We evaluated 258 patients with CML in chronic phase at 3, 6, and 12 months after the initiation of imatinib therapy. For patients not in complete cytogenetic remission, the probability of a subsequent complete cytogenetic remission markedly decreased while the risk of progression increased at each time point (Table 1Table 1Prognostic Importance of Bone Marrow Cytogenetic Analysis 3, 6, and 12 Months after the Start of Imatinib Therapy.). These results demonstrate the prognostic importance of bone marrow cytogenetic analysis during the first year of therapy. The increased risk of progression among patients not in complete cytogenetic remission after 12 months of imatinib therapy supports the introduction of therapeutic strategies that provide higher rates of early responses.

Alfonso Quintás-Cardama, M.D.
Hagop Kantarjian, M.D.
Jorge Cortes, M.D.
M.D. Anderson Cancer Center, Houston, TX 77030
aquintas@mdanderson.org

Drs. Kantarjian and Cortes report receiving research grant support from Novartis and Bristol Myers-Squibb. No other potential conflict of interest relevant to this letter was reported.

1 References

1. 1

   Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-2417
   Full Text | Web of Science | Medline

Author/Editor Response

Defuentes and colleagues call attention to possible thyroid dysfunction after therapy with imatinib and other tyrosine kinase inhibitors. Perhaps the most comprehensive analysis was that of Desai et al., who reported that thyrotropin levels increased in 62% of 42 patients with GIST who were treated with sunitinib and that hypothyroidism developed in 36%.1 These patients received sunitinib after treatment with imatinib had failed, and all of them had normal thyrotropin levels before sunitinib treatment, suggesting a minimal effect, if any, of imatinib on thyroid function. There are few reports of thyroid dysfunction after imatinib therapy, and this side effect is not mentioned in the package insert or prescribing information. Nonetheless, there have been no systematic studies in which thyroid function was monitored serially in patients receiving imatinib, and such a study would be of interest. Certainly, thyroid function should be assessed in patients with unusual fatigue or fluid retention.

Clinical trials of imatinib given either as initial therapy or after failure of interferon treatment in patients with CML have shown that it is necessary to achieve a complete cytogenetic remission in order to maximize the long-term benefit. There remains some debate about whether the rapidity with which a complete cytogenetic remission is achieved or the “depth” of remission as assessed by RT-PCR will help identify patients in complete cytogenetic remission who are destined to have a relapse and require either transplantation or a switch to dasatinib or other new tyrosine kinase inhibitors. As Quintás-Cardama et al. emphasize, it is important to monitor the response serially during the first year. This can be done by means of peripheral-blood examination with the use of either fluorescence in situ hybridization (FISH) or a reliable quantitative RT-PCR assay for BCR-ABL, with bone marrow cytogenetic analysis performed to confirm complete cytogenetic remission when the FISH result is negative or the transcript numbers have decreased to a level corresponding to a complete cytogenetic remission.

Charles A. Schiffer, M.D.
Wayne State University School of Medicine, Detroit, MI 48302
schiffer@karmanos.org

1 References

1. 1

   Desai J, Yassa L, Marqusee E, et al. Hypothyroidism after sunitinib treatment for patients with gastrointestinal stromal tumors. Ann Intern Med 2006;145:660-664
   Web of Science | Medline

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1. 1

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