A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis.

In this phase 2 open-label randomized study, 31 patients with intermediate-2 or high-risk myelofibrosis received fedratinib 300, 400 or 500 mg once daily in consecutive 4-week cycles. Mean spleen volume reductions at 12 weeks (primary end point) were 30.3% (300 mg), 33.1% (400 mg) and 43.3% (500 mg). Spleen response rates (patients achieving ⩾35% spleen reduction) at 12/24 weeks were 30%/30% (300 mg), 50%/60% (400 mg) and 64%/55% (500 mg), respectively. By 4 weeks, improvements in myelofibrosis (MF)-associated symptoms were observed. At 48 weeks, 68% of patients remained on fedratinib and 16% had discontinued because of adverse events (AEs). Common grade 3/4 AEs were anemia (58%), fatigue (13%), diarrhea (13%), vomiting (10%) and nausea (6%). Serious AEs included one case of reversible hepatic failure and one case of Wernicke's encephalopathy (after analysis cutoff). Fedratinib treatment led to reduced STAT3 phosphorylation but no meaningful change in JAK2V617F allele burden. Significant modulation (P<0.05, adjusted for multiple comparisons) of 28 cytokines was observed, many of which correlated with spleen reduction. These data confirm the clinical activity of fedratinib in MF. After the analysis cutoff date, additional reports of Wernicke's encephalopathy in other fedratinib trials led to discontinuation of the sponsored clinical development program.

Relationship among circulating tumor cells, CEA and overall survival in patients with metastatic colorectal cancer.

BACKGROUND: We previously reported results of a prospective trial evaluating the significance of circulating tumor cells (CTCs) in patients with metastatic colorectal cancer (mCRC). This secondary analysis assessed the relationship of the CTC number with carcinoembryonic antigen (CEA) and overall survival. PATIENTS AND METHODS: Patients with mCRC had CTCs measured at baseline and specific time points after the initiation of new therapy. Patients with a baseline CEA value ≥ 10 ng/ml and CEA measurements within ± 30 days of the CTC collection were included. RESULTS: We included 217 patients with mCRC who had a CEA value of ≥ 10 ng/ml. Increased baseline CEA was associated with shorter survival (15.8 versus 20.7 months, P = 0.012). Among all patients with a baseline CEA value of ≥ 25 ng/ml, patients with low baseline CTCs (<3, n = 99) had longer survival than those with high CTCs (≥ 3, n = 58; 20.8 versus 11.7 months, P = 0.001). CTCs added prognostic information at the 3-5- and 6-12-week time points regardless of CEA. In a multivariate analysis, CTCs at baseline but not CEA independently predicted survival and both CTCs and CEA independently predicted survival at 6-12 weeks. CONCLUSIONS: This study demonstrates that both CEA and CTCs contribute prognostic information for patients with mCRC.

Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer.

BACKGROUND: We demonstrated that circulating tumor cell (CTC) number at baseline and follow-up is an independent prognostic factor in metastatic colorectal cancer (mCRC). This analysis was undertaken to explore whether patient and treatment characteristics impact the prognostic value of CTCs. PATIENTS AND METHODS: CTCs were enumerated with immunomagnetic separation from the blood of 430 patients with mCRC at baseline and on therapy. Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of > or = 3 or <3 CTCs/7.5 ml, respectively. Subgroups were analyzed by line of treatment, liver involvement, receipt of oxaliplatin, irinotecan, or bevacizumab, age, and Eastern Cooperative Oncology Group performance status (ECOG PS). RESULTS: Seventy-one percent of deaths have occurred. Median follow-up for living patients is 25.8 months. For all patients, progression-free survival (PFS) and overall survival (OS) for unfavorable compared with favorable baseline CTCs is shorter (4.4 versus 7.8 m, P = 0.004 for PFS; 9.4 versus 20.6 m, P < 0.0001 for OS). In all patient subgroups, unfavorable baseline CTC was associated with inferior OS (P < 0.001). In patients receiving first- or second-line therapy (P = 0.003), irinotecan (P = 0.0001), having liver involvement (P = 0.002), >/=65 years (P = 0.0007), and ECOG PS of zero (P = 0.04), unfavorable baseline CTC was associated with inferior PFS. CONCLUSION: Baseline CTC count is an important prognostic factor within specific subgroups defined by treatment or patient characteristics.

Chemo-irradiation induced aortoesophageal fistula.

A patient with squamous cell carcinoma of the esophagus developed fatal aortoesophageal (AE) fistula following a preoperative course of combined chemotherapy plus radiation therapy. This is the first reported case of AE fistula following preoperative chemoradiotherapy. This complication is potentially correctable if suspected early, since the massive hemorrhage characteristic of AE fistula is usually preceded by an initial sentinel hemorrhage. The cause of this complication is not clear, but it may be due to inflammation of the vasa vasorum with necrosis of the aortic wall. The concomitant use of fluorouracil and cisplatin with radiation therapy acts as a radiosensitizer and may have potentiated the radiation effect on the aortic wall.

Coexistence of essential thrombocythemia and chronic lymphocytic leukemia.

A patient with chronic lymphocytic leukemia (CLL) and essential thrombocythemia is described. The two disorders were diagnosed synchronously. This association was not treatment related. Review of the literature revealed an additional 9 case reports of CLL associated with myeloproliferative disorders, but none with essential thrombocythemia.

Pulmonary hamartoma syndrome.

We reviewed 24 charts of patients with pulmonary hamartoma; numerous congenital anomalies and benign tumors were observed in this series. Most of the observed associations are known to occur in patients with Cowden's syndrome, which is characterized by multiple hamartomatous neoplasms of ectodermal, mesodermal, and endodermal origin; however, to our knowledge, there has been no reported association between pulmonary hamartoma and Cowden's syndrome. We conclude that pulmonary hamartomas are frequently accompanied by other developmental abnormalities and benign tumors.

Acute leukemia after adjuvant chemotherapy for breast cancer.

Alkalating chemotherapeutic agents are frequently implicated in the development of acute non-lymphocytic leukemia. A case report illustrates the danger of administering a prolonged course of adjuvant chemotherapy with Melphalan following mastectomy for breast cancer.

Severe febrile reaction to isoniazid.

A case of severe febrile reaction to INH is described. The patient had a mild febrile reaction two weeks following INH prophylaxis. Isoniazid was discontinued. Two weeks later and on rechallenge with INH she developed a severe febrile reaction with protracted hypotension. An initial mild febrile reaction to INH is a warning sign that rechallenge can result in a life-threatening situation.