Nicholas J. Sarlis

A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46–0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13–0.63). Both patients with intermediate-2– or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2–risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544)

Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes.

Purpose Ruxolitinib is an oral Janus kinase (JAK) 1/JAK2 inhibitor approved in the US for the treatment of intermediate-or high-risk myelofibrosis (MF). Because thrombopoietin and erythropoietin signal through JAK2, dose-dependent cytopenias are expected with treatment. In the COMFORT-I (COntrolled Myelofibrosis study with ORal JAK inhibitor Treatment I) trial, these cytopenias were effectively managed with dose adjustments. These analyses were conducted to evaluate the relationship between ruxolitinib titrated doses and changes in platelet count and hemoglobin level as well as efficacy measures. Patients and methods COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 109/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die [BID]) for patients with baseline platelet counts of 100–200 × 109/L and >200 × 109/L, respectively. Percentage changes from baseline to week 24 in spleen volume and MF-related symptoms were assessed in subgroups defined by final titrated dose (average daily dose during weeks 21 to 24). Results The median final titrated doses for patients starting at doses of 15 and 20 mg BID were 10 and 20 mg BID, respectively, at week 24. Most dose reductions occurred in the first 8–12 weeks of treatment and coincided with decreases in platelet count and hemoglobin level. Subsequently, platelet counts stabilized and hemoglobin levels gradually returned to near baseline levels (red blood cell transfusion rates followed a similar trend). Final titrated doses of ≥10 mg BID were associated with clinically meaningful improvements in MF-related symptoms that were comparable across doses, while marginally greater reductions in spleen volume were observed at higher doses. Conclusion This COMFORT-I analysis shows that dose-dependent cytopenias were effectively managed with ruxolitinib dose adjustments, and titrated doses of ≥10 mg BID were associated with clinically meaningful reductions in spleen volume and symptom improvement at week 24.

Progressive burden of myelofibrosis in untreated patients: assessment of patient-reported outcomes in patients randomized to placebo in the COMFORT-I study.

Patient-reported outcomes (PROs) and spleen size in patients not receiving therapy (N=154) in COMFORT-I, a randomized, double-blind study of the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis were evaluated. Baseline PROs indicated considerable disease burden. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 scores, modified Myelofibrosis Symptom Assessment Form v2.0 Total Symptom Score, and Patient Reported Outcome Measurement Information System Fatigue scores worsened from baseline through week 24. At weeks 4 and 24, 18.3 and 40.2% of patients evaluated their condition as having worsened from baseline on the Patient Global Impression of Change questionnaire. Spleen volume and palpable length increased in most patients. These results demonstrate the progressive and debilitating effects of myelofibrosis. The consequences of delayed intervention should be assessed in the management of patients with myelofibrosis and treatment should be considered as clinically indicated for symptomatic relief or splenomegaly control.

Ruxolitinib, an oral JAK1 and JAK2 inhibitor, in myelofibrosis.

Introduction: Myelofibrosis (MF) is a debilitating hematologic malignancy characterized by progressive splenomegaly, burdensome symptoms, cytopenias and shortened survival. Chronic alterations in Janus-associated kinase-signal transducer and activator of transcription (JAK-STAT) signaling have been identified in the pathogenesis of MF, making this pathway a target for drug development. Ruxolitinib is the first JAK1 and JAK2 inhibitor to be approved by the US Food and Drug Administration. Areas covered: This review describes the characteristics of MF, the current therapeutic options and need for effective therapies, the contribution of aberrant JAK-STAT signaling to various disease-specific manifestations and the pharmacodynamics, pharmacokinetics, efficacy and tolerability of ruxolitinib. Articles describing MF disease burden and results of ruxolitinib pre-clinical and clinical trials were identified and summarized. Expert opinion: Conventional MF treatments alleviate some MF symptoms but have limited efficacy, do not modify the natural history of the disease and are not approved for MF. The JAK1 and JAK2 inhibitor ruxolitinib has shown promising results in pre-clinical and clinical trials. In Phase III trials, ruxolitinib was shown to reduce splenomegaly and improve MF-related symptoms. Recent evidence also suggests that ruxolitinib may improve survival. The most common adverse events were anemia and thrombocytopenia, which were managed with dose adjustments (or red blood cell transfusions for anemia).

Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes

Myelofibrosis (MF) is a rare chronic BCR-ABL1 (breakpoint cluster region-Abelson murine leukemia viral oncogene homologue 1)-negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, inefficient hematopoiesis, and shortened survival. The clinical manifestations of MF include splenomegaly, consequent to extramedullary hematopoiesis, cytopenias, and an array of potentially debilitating abdominal and constitutional symptoms. Dysregulated Janus kinase (JAK)-signal transducer and activator of transcription signaling underlies secondary disease-associated effects in MF, such as myeloproliferation, bone marrow fibrosis, constitutional symptoms, and cachexia. Common fatal complications of MF include transformation to acute leukemia, thrombohemorrhagic events, organ failure, and infections. Potential complications from hepatosplenomegaly include portal hypertension and variceal bleeding, whereas extramedullary hematopoiesis outside the spleen and liver – depending on the affected organ – may result in intracranial hypertension, spinal cord compression, pulmonary hypertension, pleural effusions, lymphadenopathy, skin lesions, and/or exacerbation of abdominal symptoms. Although allogeneic stem cell transplantation is the only potentially curative therapy, it is suitable for few patients. The JAK1/JAK2 inhibitor ruxolitinib is effective in improving splenomegaly, MF-related symptoms, and quality-of-life measures. Emerging evidence that ruxolitinib may be associated with a survival benefit in intermediate- or high-risk MF suggests the possibility of a disease-modifying effect. Consequently, ruxolitinib could provide a treatment backbone to which other (conventional and novel) therapies may be added for the prevention and effective management of specific MF-associated complications.

Acetylated Tubulin (AT) as a Prognostic Marker in Squamous Cell Carcinoma of the Head and Neck

Acetylated tubulin (AT) expression has been proposed as a marker for sensitivity to taxane chemotherapy. We wanted to explore AT as a prognostic marker in squamous cell carcinoma of the head and neck (SCCHN). We assessed AT expression in archival tissue from our institutional tissue bank of primary SCCHN specimens. We also examined AT expression on pre-therapy tissues of patients with SCCHN receiving induction chemotherapy with docetaxel, cisplatin and 5FU (TPF IC). AT expression was assessed on archival cases of SCCHN with (Nxa0=xa063) and without (Nxa0=xa082) locoregional lymph node metastases (LNM). The predominant tumor site was oral cavity (52xa0%). Immunohistochemistry staining was based on staining intensity and percentage of tumor cells stained to create a weighted index (WI). A total of nine patients who received TPF IC were evaluable for response by RECIST and also had pre-therapy tissues available. A significant independent correlation between AT and tumor grade (pxa0=xa00.001) and primary location (pxa0=xa00.008) was noted. There was a trend of higher AT in patients with presence of LNM (pxa0=xa00.052) and a trend in improved OS for patients with an AT WI below the median compared to those above the median for patients with no LNM (pxa0=xa00.054). For patients treated with induction TPF, we observed an inverse correlation between AT expression and response to TPF IC (pxa0=xa00.0071). AT expression is correlated with tumor grade and primary site. There was an observed trend correlating AT with presence nodal metastases. The observed inverse correlation with response to taxane based chemotherapy needs validation in a larger sample size.

Symptom burden and splenomegaly in patients with myelofibrosis in the United States: a retrospective medical record review

Myelofibrosis (MF) is a clonal hematopoietic malignancy characterized by constitutional and localized symptoms, progressive splenomegaly, bone marrow fibrosis, and cytopenias. Although MF is well studied, few studies exist regarding its symptomatic burden in routine clinical practice. This study aimed to characterize symptoms and other clinical features of MF among patients in the United States. We conducted a retrospective medical record review of adult patients with an MF diagnosis between 1 January 2005 and 31 March 2010, stratified by the presence of palpable splenomegaly. Eligible patients had 12 months or more of follow‐up after diagnosis (or after detection of splenomegaly, if present) unless death occurred. Demographic and clinical characteristics, MF‐related symptoms, and treatments were reported by treating physicians. We report on 180 MF patients: 102 with splenomegaly, 78 without. Median age was 66 years, 63% were male, and 82% had intermediate‐2 or high‐risk MF (International Prognostic Scoring System). Fatigue was reported by ~85% of patients; weight loss, night sweats, and fever (any grade) were each reported by 50% or more of patients. Generalized abdominal pain, left subcostal pain, and early satiety occurred more frequently among patients with splenomegaly. Multiple symptoms were reported by 95% of patients. Common comorbidities were hypertension, diabetes, and chronic pulmonary disease. Symptoms are common in MF patients, regardless of the presence of palpable splenomegaly. Careful assessment of symptom burden is an important aspect of the clinical evaluation of patients with MF.

Patterns of hydroxyurea use and clinical outcomes among patients with polycythemia vera in real-world clinical practice: a chart review

BackgroundHydroxyurea (HU) is among the most commonly used cytoreductive treatments for polycythemia vera (PV), but previous research and clinical experience suggest that not all patients respond optimally, consistently, or durably to HU treatment. This study investigated patterns of HU use and impact on disease control among patients with PV in real-world clinical practice in the United States.MethodsOncologists and hematologists recruited between April and July 2014 reported data from patient charts. Treatment history and disease symptom comparisons between HU subgroups were performed using Chi square tests or one-way analyses of variance for categorical and continuous variables. Other analyses were performed using descriptive statistics.ResultsOverall, 329 physicians participated and provided data on 1309 patients with PV (62.3xa0% male; mean agexa0=xa062.5xa0years, mean time since diagnosisxa0=xa05.2xa0years). In the 229 (17.5xa0%) patients who had stopped HU, the most common reasons for HU discontinuation—as assessed by the treating clinician—were inadequate response (29.3xa0%), intolerance (27.5xa0%), and disease progression (12.7xa0%). Among patients currently on HU, a significant proportion had elevated blood cell counts: 34.4xa0% had hematocrit values ≥45xa0%, 59.4xa0% had platelet levels >400xa0×xa0109/L, and 58.2xa0% had WBC counts >xa010xa0×xa0109/L. Two-thirds (66.3xa0%) of patients had ≥1 elevated count, 40.3xa0% had ≥2 elevated counts, and 19.8xa0% had all 3 counts elevated. The most common PV-related signs and symptoms among all patients were fatigue and splenomegaly.ConclusionsAlthough many patients with PV benefit from HU therapy, some continue to have suboptimal control of their disease, as evidenced by persistence of abnormally elevated blood cell counts and the continued experience of disease-related manifestations (signs and symptoms). These data further denote a significant medical need for some patients with PV currently or previously treated with HU.

Functional polymorphisms in the insulin-like binding protein-3 gene may modulate susceptibility to differentiated thyroid carcinoma in Caucasian Americans†

The insulin‐like growth factor (IGF) pathway is believed to play a pivotal role in thyroid carcinogenesis. Polymorphisms of IGF‐1 and IGF binding protein‐3 (IGFBP‐3) have been associated with modulation of risk for the emergence of assorted common malignancies, but studies of the influence of such polymorphisms on risk of differentiated thyroid carcinoma (DTC) are lacking. In a case–control study of 173 DTC patients, 101 patients with benign thyroid disease, and 401 controls, an unconditional logistical regression model adjusted for age and sex was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between polymorphisms of IGF‐1 and IGFBP‐3 and DTC risk. IGFBP‐3 rs2132572 GA/AA genotypes were associated with a decreased risk of DTC (adjusted ORu2009=u20090.6, 95% CI: 0.4–0.9), particularly multifocal DTC (adjusted ORu2009=u20090.3, 95% CI: 0.1–0.7). The association with DTC was more evident in subjects with a first‐degree family history of cancer (adjusted ORu2009=u20090.4, 95% CI: 0.2–0.7, Pinteractionu2009=u20090.013) and non‐drinkers (adjusted ORu2009=u20090.4, 95% CI: 0.2–0.7, Pinteractionu2009=u20090.028). A four single nucleotide polymorphism haplotype of IGFBP‐3 was associated with a decreased risk of DTC (adjusted ORu2009=u20090.7, 95% CI: 0.5–1.0, Pu2009=u20090.030). Our study suggests that polymorphic IGFBP‐3 may be involved in susceptibility to DTC.