Rapid and Complete Control of Idiopathic Hypereosinophilia with Imatinib Mesylate
September 7, 2001
In this case report, we report what we believe to be the first case of imatinib mesylate or STI-571 (Novartis) use for treatment of idiopathic hypereosinophilia syndrome (HES). HES is often a fatal illness, damaging the heart, nervous system, lungs, liver, and kidneys. It is often treated with interferon-alpha. In this patient, it was combined with hydroxyurea, and we believe it saved his life. However, he experienced many common side effects, such as a profound intractable headache, severe fatigue, and concentration difficulties. After years on hydroxyurea and interferon-alpha, the severity of these side effects motivated us to try a trial of imatinib mesylate. Its use was followed by an abrupt remission of HES in a few weeks, with no significant side effects.
HES is a rare, highly lethal, and heterogeneous hypereosinophilic disorder. Eosinophils are normally 1% to 3% of blood leukocytes. High eosinophil counts may be caused by parasitic infections, atopy, hypersensitivity reactions, collagen vascular diseases, or tumors. In contrast, HES has no known cause. It can occur in any decade of life, but tends to occur before age 50 years, in early adulthood. HES also produces significant end-organ damage: cardiac 90%, central and peripheral nervous system 65%, pulmonary 50%, liver and spleen 35%, kidneys 25%, and retina 90%. Survival times in the past were as low as 9 months. In 1989, survival rates were still only 80% at 5 years and 42% at 10 years.
Diagnostic criteria include: persistent eosinophilia of > 1500 eosinophils over 6 months in the absence of known etiologies (eg, parasites, L-tryptophan-associated eosinophilia myalgia syndrome, or allergies), plus signs and symptoms of organ involvement. Patients who survive must plan on chronic treatment for the rest of their lives.
Imatinib Mesylate (STI-571 or Gleevec)
Imatinib mesylate, or STI-571 (signal transduction inhibitor number 571), is a potent and selective inhibitor for abl kinases, including bcr-abl, c-kit, and the platelet-derived growth factor receptor tyrosine kinases. It represents a specific new generation of protein targeted cancer treatments which operate in contrast to traditional chemotherapeutic agents.
Imatinib mesylate has a dose-dependent side effect profile. No dose has been established for HES, but our doses under 100 mg have produced no current side effects. Doses of 300 mg per day have produced significant nausea, edema, and myalgia in 25% of patients with chronic myeloid leukemia (CML). Doses between 300 mg and 1000 mg can cause a 47% risk of severe neutropenia and a 38% risk of thrombocytopenia.
Imatinib mesylate is an oral tyrosine kinase inhibitor that received accelerated approval from the US Food and Drug Administration (FDA) for treatment of CML in blast crisis, accelerated phase, or chronic phase after failure of interferon-alpha.[10-12] It is used in gastrointestinal stromal tumors (C.A. Muro-Cacho, personal communication, July 2001), and proposed for small cell lung cancer and skin neoplasms.[15,16] (Tyrosine kinase inhibitors and signal transduction inhibitors have also been proposed as future treatments for prostate cancer,[17,18] arteriosclerosis, and psoriasis.)
A 41-year-old single businessman with no significant medical history prior to June 1993 developed a regular morning dry cough and severe jaw and tooth pain that was unexplained by multiple dentists. A complete blood count (CBC) revealed 35% eosinophils. An extensive evaluation for etiologies included 3 bone marrow biopsies, extensive titers for parasites, immunoglobulin levels, a tuberculosis tine test, pulmonary function tests, echocardiogram, and full body computed tomography scans. An excisional biopsy of the mental nerve found a hyper proliferation of eosinophils. Initial medical treatment was prednisone 60 mg per day.
In 1994, the patient had a sudden right-sided limb weakness, an episode of amaurosis in his left eye, and intermittent paraesthesia in his fingers, toes, and thigh, which worsened over 36 hours. Magnetic resonance imaging (MRI) of the head revealed a 4-mm left cerebral hemisphere infarct due to hypereosinophilia "sludging" — his eosinophil levels had reached 18,000 and 44% of his white blood cell count (WBC). No neutrophils could be identified on manual slide exam. The infarct was believed to be due to peripheral embolism — most likely from his heart. The patient was treated with intravenous methylprednisolone, heparin, and later warfarin, alpha-interferon, and hydroxyurea. The eosinophil levels ultimately decreased. He was able to function in his managerial role on only interferon and hydroxyurea, at the lowest possible doses — 900,000 IU interferon-alpha subcutaneously daily, and 500 mg hydroxyurea every other day. Multiple attempts at lowering either medication caused a prompt and significant rise in his eosinophils within 1 to 2 weeks.
On these 2 medications, the patient's eosinophils ranged from 25% to 65% (1100 to 2500), while he showed global suppression of other CBC parameters, such as neutrophils and platelets. His WBC ranged between 3500/mcL and 4000/mcL, his neutrophils between 2600/mcL and 3900/mcL, and his platelets between 35,000/mcL and 110,000/mcL. Upon starting these 2 medications, he developed borderline hypothyroidism and low free and total testosterone serum levels.
Eventually, he became disillusioned with the side effects of his treatment — particularly severe headaches that started immediately after initiation of his interferon-alpha. These were unresponsive to treatment with more than 20 agents, prescribed by 3 headache specialists. His MRI showed no new findings. We eventually found that the headaches correlated with eosinophil cationic protein (ECP) levels — both his ECP and headaches decreased 70% with theophylline (J.L. Schaller, G.A.Burkland, unpublished data, 2001). Nevertheless, he struggled with residual headache pain, profound fatigue, "flu-like feelings," anorexia, insomnia, hair loss, and marked boredom. These side effects were treatment resistant to any pharmacologic intervention.
Imatinib Mesylate Use in an HES Patient
Informed Consent and Method
The patient started treatment with imatinib mesylate (STI-571, Gleevec) 100 mg orally per day. The imatinib mesylate trial was not based on tyrosine kinase laboratory testing (eg, c-kit testing). Imatinib mesylate was initiated because it is used for CML, and both HES and CML have been hypothesized to have a common regulatory association. Further, since both HES and CML are treated with interferon-alpha, it was thought possible that imatinib mesylate benefit for CML might extend to HES. If it only reduced his daily interferon-alpha, it might improve his quality of life due to less interferon side effects. His starting dose was low and both interferon-alpha and hydroxyurea initially were kept at the same dose.
This patient was treated as an individual. As in many instances in the practice of medicine, because the usual treatment of his illness was unsatisfactory, we tried a new therapy. No Institutional Review Board approval was sought as this was considered patient care and not a research project. The patient was fully informed about what we were doing and about the fact that it had not been done before and that we did not know what would happen. Under these circumstances, which are fully in accord with the Helsinski Declaration on human clinical care, the patient was provided a fully informed consent in writing, which was signed. Once we observed the remarkable result, we believed that it would be unethical not to publish these observations quickly, a decision with which the editors of Medscape General Medicine concur. Since HES is so rare, it is unlikely a blind, placebo-controlled trial will be conducted in the next 2 years, if ever. Due to the small numbers of HES patients, a MEDLINE review shows most HES clinical publications are single case reports or case series studies.
The patient's severe side effects on his current treatment motivated his treatment. Using imatinib mesylate was merely an attempt at relieving suffering. If his eosinophils declined and he was able to reduce or eliminate his current medications, the quality of life offered the patient might improve. Specifically, he might experience a reduction of intractable headaches and severe fatigue. The mere possibility of decreasing his severe unremitting headache pain was felt by the patient and consulting physicians to be in excess of any risk of using low-dose imatinib mesylate. The potential benefits to the patient included: a reduction in his baseline hypereosinophilia, the reduction of suffering, ending iatrogenic hormone suppression, an option to remove or reduce his current treatment, and a therapeutic option should his current medications cease to function.
Further, the patient's relationship with all physicians was unaffected by his decision to use or abstain from the imatinib mesylate. Indeed, the patient insisted on a trial after reading a major newspaper article and MEDLINE articles on the medication's use in CML.
The patient's informed consent was multifaceted and extensive. Specifically, over 6 years he has regularly read medical articles on HES provided by 4 physicians consulting in his care and from his own investigation. These publications were from MEDLINE, pre-MEDLINE, and academic textbooks. He has read extensively on major HES treatment agents. The patient carefully read more than 20 publications on imatinib mesylate, and these were reviewed with him in detail over 3 months. He was aware the use of imatinib mesylate for HES had not been systematically studied, and that we could not find a case report of HES treated with imatinib mesylate. Therefore, the outcome of his trial would be unknown. The patient read the FDA-approved uses for imatinib mesylate and understood that it had not been studied or approved for HES. The product labeling was read completely on 3 separate occasions.
He understood all major and common side effects of imatinib mesylate, including side effects occurring increasingly at higher doses. Further, he discussed the use of imatinib mesylate with 2 hematologists, so that he would not be manipulated by dependence. His decision was not affected by major depression or cognitive impairment, according to standard major depression research scales and repeated interviews by a board-certified psychiatrist. One close family member was included in the summaries of all critical discussions and agreed that the trial was reasonable. We received consent to talk with multiple relatives by phone, and they independently confirmed the patient was suffering for years. When in pain, he told them it was "medication side effects."
In summary, the patient made a fully informed consent with significant understanding of the medication. He understood the theoretical mechanism for imatinib mesylate, its common and severe side effects, and its lack of FDA approval for use in HES.
His trial was initiated and monitored every 1 to 2 weeks by 2 hematologists familiar with his disease. He had weekly contact with us, and the data generated are outlined in Table 1.
These eosinophil values represent his lowest eosinophil levels in more than 6 years with an average of 30-45 CBC evaluations per year.
Further, clinical improvements include a 95% decrease in his thick sputum production. His "skin blotches," pimples, and kerototic skin thickening have decreased. His nails are less brittle and less easily chipped.
His only initial side effect was mild nausea on 100 mg of imatinib mesylate, relieved with ondansetron 8 mg per day, but this side effect is now gone. During the past 6 weeks, he gradually developed a constant mild headache. Since his eosinophils remained at 0% to 2%, his dose was reduced to 75 mg per day (three 25-mg capsules compounded with an inert filler). His headache stopped with the dose reduction.
It is hypothesized that the higher doses of imatinib mesylate used for CML may not be necessary for HES, since this patient's 75 mg daily seems effective at maintaining normal eosinophil levels in the absence of both interferon-alpha and hydroxyurea (for a month). The lowest effective dose for this patient's HES is unknown.
While it is unlikely his marked improvements are due to chance, the duration of these benefits from imatinib mesylate in HES is not known. Since high mortality rates exist for HES even after 5 years, regular CBC and differential evaluations should be done to identify any relapse. In the event of a relapse, there has been the suggestion in CML literature that adding other tyrosine kinase inhibitors to imatinib mesylate may improve efficacy,[21, 22] but this has not been systematically studied in HES.
The surprising and rapid control with imatinib mesylate in dangerous HES made prompt reporting ethical. Spontaneous remissions are not reported as features of HES. Aggressive chemotherapeutic agents can reduce eosinophil levels and successfully control the disease. However, sustained remission without treatment is an exceptional occurrence.[23,24] While it is unlikely our patient had a spontaneous remission, starting within days of starting imatinib mesylate, it cannot be definitively ruled out. Obviously, at least a pilot case series of this treatment must be done before this patient's experience is seen as applicable to other HES patients.
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Authors and Disclosures
James L. Schaller, MD, MAR, is President, Chester County Research Center, Chester Springs, Pennsylvania. Glenn A. Burkland, DMD, is Associate Clinical Professor, Temple University School of Dental Medicine, Philadelphia, Pennsylvania.
Medscape General Medicine. 2001;3(3) © 2001 Medscape