Patricia Ault

The effects of imatinib on pregnancy outcome

Imatinib has now been in use for almost 10 years. Despite this cumulative experience, little is known about its effects on pregnancy; as a result, there are few published data to facilitate the counseling of women who conceive while taking imatinib. The results we now present provide information which may be of use in such circumstances. Of 180 women exposed to imatinib during pregnancy, outcome data are available for 125 (69%). Of those with known outcomes, 50% delivered normal infants and 28% underwent elective terminations, 3 following the identification of abnormalities. There were a total of 12 infants in whom abnormalities were identified, 3 of which had strikingly similar complex malformations that are clearly a cause for concern. It appears that although most pregnancies exposed to imatinib are likely to have a successful outcome, there remains a risk that exposure may result in serious fetal malformations.

Pregnancy Among Patients With Chronic Myeloid Leukemia Treated With Imatinib

PURPOSE Imatinib has potential teratogenicity in animals, but the effect of exposure to imatinib during conception and pregnancy in humans is not known. PATIENTS AND METHODS The records of all patients with chronic myeloid leukemia (CML) treated with imatinib were reviewed. We report the experience on 19 pregnancies involving 18 patients (10 females and eight males) who conceived while receiving imatinib for the treatment of CML. RESULTS All female patients discontinued therapy immediately on recognition of pregnancy. Three pregnancies (involving two female patients and one male patient) ended in spontaneous abortion, and one patient had an elective abortion. All other pregnancies were uneventful. Two of the 16 babies had minor abnormalities at or shortly after birth (hypospadias in one baby and rotation of small intestine in one baby) that were surgically repaired. All babies have continued normal growth and development. Among female patients who interrupted therapy, five of nine in complete hematologic remission (CHR) at the time of treatment interruption eventually lost CHR, and six experienced an increase in Philadelphia chromosome-positive metaphases. At a median of 18 months after resuming therapy with imatinib, eight patients had a cytogenetic response (complete in three patients). CONCLUSION Although there is no evidence that a brief exposure to imatinib during conception and pregnancy adversely affects the developing fetus, most patients lose their response after treatment interruption. Patients receiving imatinib should be advised to practice adequate contraception.

Response of idiopathic hypereosinophilic syndrome to treatment with imatinib mesylate

Idiopathic hypereosinophilic syndrome (HES) is a rare hematologic disorder characterized by persistent eosinophilia with organ involvement. Patients with HES have a poor prognosis, but the disease course can be heterogeneous. Treatment of HES has included corticosteroids, chemotherapeutic agents such as cyclophosphamide, vincristine, hydroxyrea, and most recently interferon-alpha (IFN-alpha) which has shown long-term beneficial effects. We herein report on a patient with HES who had disease resistant to steroids, and chemotherapy with 2-chlorodeoxyadenosine and cytarabine, but who had a significant response after only 8 days of treatment with imatinib mesylate 100mg daily. The possible mechanism of response is discussed. This observation may lead to a better understanding of the pathophysiology of HES, and may provide a new form of effective therapy for the disease.

Measuring the symptom burden associated with the treatment of chronic myeloid leukemia

We developed a module of the MD Anderson Symptom Inventory (MDASI) for patients with chronic myeloid leukemia (CML). To develop the MDASI-CML, we identified CML-specific symptoms from qualitative interviews with 35 patients. A list of candidate symptoms was reduced by a panel of patients, caregivers, and clinicians to the 13 core MDASI symptom items and 6 CML-specific items; these items were subsequently administered to 30 patients. Cognitive debriefing confirmed that the items were clear, relevant, and easy to use. One additional CML-specific symptom item was added, for a total of 7. The refined MDASI-CML was administered to 152 patients once every 2 weeks for 1 year. The content, concurrent, known-group, and construct validity of the MDASI-CML were evaluated. The internal consistency and test-retest reliabilities of the module were adequate. Longitudinal analysis showed relatively stable symptom severity scores over time. The most severe symptoms were fatigue, drowsiness, disturbed sleep, muscle soreness and cramping, and trouble remembering things. Approximately one-third of the patients who completed the MDASI-CML reported persistent moderate-to-severe symptoms. The MDASI-CML is a valid and reliable symptom assessment instrument that can be used in clinical studies of symptom status in patients with CML.

Successful Completion of Pregnancy in a Patient With Chronic Myeloid Leukemia Without Active Intervention: A Case Report and Review of the Literature

The management of patients with chronic myeloid leukemia (CML) during pregnancy is a matter of continued debate. We present a 21-year-old woman in whom CML was diagnosed during early pregnancy. Because the patient was asymptomatic and desired to carry the pregnancy to term while minimizing fetal exposure to medication, she was observed with no therapy for the duration of her pregnancy. The white blood cell count showed a slow downward trend throughout her pregnancy. She delivered a healthy baby and breast fed for a time before initiating therapy for CML. We reviewed the published case reports of women who had a pregnancy occur in the setting of treatment with imatinib. Given the adverse effects of fetal exposure to imatinib as treatment for the mother with CML, close observation might be an option for selected patients who are diagnosed with CML while pregnant and who have minimal clinical manifestations of CML.

Identification of Side Effects Associated With Intolerance to BCR-ABL Inhibitors in Patients With Chronic Myeloid Leukemia

Clinical intolerance occurs when the toxicity of a medication outweighs its clinical benefit. Early recognition of clinical intolerance to BCR-ABL inhibitors used for chronic myeloid leukemia (CML) is important for maximizing patient benefit. In CML, most side effects associated with BCR-ABL inhibitor therapy are mild and easily managed, so recognizing, monitoring, and addressing serious side effects may ensure optimal outcome. However, a subset of patients will be intolerant to first-line imatinib. Patients who experience unresponsive grade 3 or any grade 4 nonhematologic side effects to imatinib may require discontinuation and switching to second-line therapies, such as dasatinib or nilotinib, after identification of intolerance. The most common side effects associated with dasatinib and nilotinib are hematologic and generally are reversible with dose adjustment. Pleural effusions are more common with dasatinib use and may be managed by dose interruption and reduction. Both drugs possess warnings regarding QT prolongation, but nilotinib carries a black box warning for QT prolongation and sudden death.

Management of Molecular‐Targeted Therapy for Chronic Myelogenous Leukemia

Purpose To provide primary care providers with guidelines on the evaluation and manage‐ment of treatment for patients with chronic myelogenous leukemia (CML) with emphasis on the molecular‐targeted therapy imatinib mesylate. Data Sources Research‐based articles in the medical literature, review articles, and clinical practice guidelines. Conclusions CML is a clonal stem cell disorder causing 5,000 new cases annually. Research on mol‐eculartargeted therapy confirms that specific protein kinases have broad conse‐quences for the development of future drugs to treat CML. The most recent discovery is a new compound, imatinib mesylate, which has become commercially available. Currently, the standard of care for CML is this agent. This therapy has changed management strategies for treatment of patients with the diagnosis of CML. Implications for Practice Long‐term observations and evaluations are needed for final determination of treatment effectiveness; thus, primary care providers will follow patients with CML in the community. Unforeseen toxicity may surface, requiring accurate assessment and evalua‐tion. Primary care providers will be actively involved with providing symptom management for these patients.

Pregnancy in a patient with hypereosinophilic syndrome.

Hypereosinophilic syndrome (HES) is a rare entity of unknown etiology that may cause a multitude of problems, from skin rash to organ failure, due to eosinophil infiltrate of tissues. Information on the interaction of hypereosinophilia and pregnancy in patients with established HES is very limited. Here we report a case of a woman with a seven year history of HES whose pregnancy resulted in the delivery of a healthy infant without complications, and no evidence of elevated eosinophils in the infants blood. During pregnancy the patient experienced significant reduction of eosinophils in her blood and resolution of signs and symptoms related to hypereosinophilia.

A new symptom measure in chronic myeloid leukemia.

e19545 Background: A major barrier to effective symptom management in chronic myeloid leukemia (CML) is inadequate assessment. We aimed to develop a short, easily-understood, valid, and reliable patient-reported outcome measure of CML symptoms for research and practice. METHODS 127 patients with CML completed the 13 symptom severity and 6 interference items of the core M. D. Anderson Symptom Inventory (MDASI) plus 7 CML-specific symptom items (Table), generated from patient and expert input, measured on a 0-10 scale (0 = none, 10 = worst imaginable). 85 patients completed the same items 2 weeks later. Patients also answered a single quality-of-life (QOL) question. Demographic and disease information was collected on all patients. Multivariate analysis examined relationships among items. Psychometric procedures determined reliability and validity of the MDASI-CML. RESULTS Sample characteristics and symptom severity and interference are in the table. All items were retained as clinically significant and nonredundant. The reliability index (Cronbach α) and test-retest reliability of the 20 symptom items were 0.94 and 0.93 respectively and of the 6 interference items were 0.94 and 0.91 respectively. The MDASI-CML discriminated between patients who were employed versus those medically disabled and with good versus poor QOL. Symptom severity explained 87% of the variance in interference, with the core symptoms explaining 83% and the CML-specific symptoms explaining 76%. CONCLUSIONS We have validated an analytic tool, the MDASI-CML, for quantifying CML symptoms. The MDASI-CML is being used to assess side effects in treatment trials and to monitor symptoms in clinical care. [Table: see text] [Table: see text].