The patient will be followed until resolution as per treating physician and reported upon resolution of symptoms. Management of Asymptomatic Decreases in LVEF. Herceptin may be continued in patients experiencing an asymptomatic absolute decrease in LVEF of <20 percentage points from baseline, when the ejection fraction remains within the imaging center’s range of normal limits. Repeat measures of LVEF should be obtained using the methodology selected at baseline. Close follow-up of such patients is recommended. Patients with an asymptomatic absolute decrease in LVEF of ≥20 percentage points (even if within the normal limits of the institution) or an ejection fraction below the range of normal limits, will be taken off treatment, but remain in the study for disease follow-up. They will be considered for treatment of incipient CHF as prescribed by the HFSA (e.g., ACE inhibitors, angiotensin-II receptor blockers, β-blockers, diuretics, and cardiac glycosides, as needed; see CONFIDENTIAL Page 20 of 102 Protocol: HERCEPTIN® + E75/GM-CSF Version 3.1 ML25749 05 March 2017 Appendix D for HFSA guidelines). In light of the variability inherent in the assessment of ejection fraction, consideration should be given to repeating the study to confirm an observed decline. Repeat measures of LVEF should be obtained using the same methodology selected at baseline. If Herceptin has been discontinued for an asymptomatic decline in LVEF, a repeat measure of LVEF will be obtained in one month to determine if the decline has resolved. Infusion-Associated Symptoms. During the first infusion with Herceptin, a symptom complex consisting of chills and/or fever is observed in approximately 40% of patients. Other signs and/or symptoms may include nausea, vomiting, pain, rigors, headache, cough, dizziness, rash, and asthenia. These symptoms are usually mild to moderate in severity, and occur infrequently with subsequent Herceptin infusions. These symptoms can be treated with an analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as diphenhydramine. Serious Infusion-Associated Events. Serious adverse reactions to Herceptin infusion including dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation and respiratory distress have been reported infrequently. In rare cases (4 per 10,000), these events were associated with a clinical course culminating in a fatal outcome. Serious reactions have been treated with supportive therapy such as oxygen, beta-agonists, corticosteroids and withdrawal of Herceptin as indicated. Hematologic Toxicity and Neutropenic Infections. In the clinical trials, an increased incidence of anemia was observed in patients receiving Herceptin plus chemotherapy compared with patients receiving chemotherapy alone. The majority of these anemia events were mild or moderate in intensity and reversible; none resulted in discontinuation of Herceptin therapy. In the clinical trials, the per-patient incidences of moderate to severe neutropenia and of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. In the post-marketing setting, deaths due to sepsis in patients with severe neutropenia have been reported in patients receiving Herceptin and myelosuppressive chemotherapy, although in controlled clinical trials (pre- and post-marketing), the incidence of septic deaths was not significantly increased. The pathophysiologic basis for exacerbation of neutropenia has not been determined; the effect of Herceptin on the pharmacokinetics of chemotherapeutic agents has not been fully evaluated. Secondary acute leukemia or myelodysplastic syndrome has been reported in 4 of approximately 1200 patients who participated in Herceptin clinical trials. Patients treated with chemotherapeutic agents are known to be at increased risk for secondary leukemia. The observed incidence of leukemia among Herceptin treated patients appears to be consistent with the expected incidence of leukemia among patients treated with chemotherapy for metastatic breast cancer. Therefore, the CONFIDENTIAL Page 21 of 102 Protocol: HERCEPTIN® + E75/GM-CSF Version 3.1 ML25749 05 March 2017 contribution of Herceptin to the etiology of acute leukemia or myelodysplastic syndrome in these cases is unclear. Management of Hematologic Toxicities.